Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study.

Introduction: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. In clinical studies, gene replacement therapy with onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) was efficacious in improving motor functioning in children with SMA. However, its effects on cognitive and language skills are largely unknown. Methods: This longitudinal observational study evaluated changes in motor and neurocognitive functioning over a 1-year period after administration of onasemnogene abeparvovec in 12 symptomatic SMA type 1 patients with two copies of SMN2 aged 1.7-52.6 months at administration. Motor functioning was measured using the Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) while neurocognitive assessment was measured using Griffiths III. Motor milestones and language ability were also assessed at each timepoint. Results and discussion: Statistically significant increases in median CHOP-INTEND scores from baseline were observed at 1, 3, 6, and 12 months after onasemnogene abeparvovec administration (all p ≤ 0.005). Most (91.7%) patients were able to roll over or sit independently for >1 min at 12 months. Significant increases in the Griffiths III Foundations of Learning, Language and Communication, Eye and Hand Coordination, and Personal-Social-Emotional subscale scores were observed at 12-months, but not in the Gross Motor subscale. Speech and language abilities progressed in most patients. Overall, most patients showed some improvement in cognitive and communication performance after treatment with onasemnogene abeparvovec in addition to significant improvement in motor functioning and motor milestones. Evaluation of neurocognitive function should be considered when assessing the global functioning of patients with SMA.

Sequential treatment with nusinersen, Zolgensma® and risdiplam in a paediatric patient with spinal muscular atrophytype 1: a case report.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that causes muscle atrophy and weakness. While no specific therapies existed until a few years ago, several effective disease-modifying treatments have become available in recent years. However, there are currently no recommendations on the management of therapy sequencing involving these new treatments. A 4-months-old girl with SMA type 1 and two copies of SMN2 was started on treatment with nusinersen resulting in significant improvement in her motor and respiratory function. However, after six doses, treatment was changed to Zolgensma® due to caregiver's decision. In the months following the administration, the patient showed significant clinical improvement in motor performance. After 12 months, the child started therapy with risdiplam in another country. One year after the start of therapy with risdiplam further improvements in both motor and bulbar functions were highlighted. This case report raises a question: is a multiple consecutive theraphy more effective than monotherapy in SMA treatment? These results suggest the need to further explore the potential efficacy of a multidrug treatment.

Clinical, Genetic, and Histological Characterization of Patients with Rare Neuromuscular and Mitochondrial Diseases Presenting with Different Cardiomyopathy Phenotypes.

Cardiomyopathies are mostly determined by genetic mutations affecting either cardiac muscle cell structure or function. Nevertheless, cardiomyopathies may also be part of complex clinical phenotypes in the spectrum of neuromuscular (NMD) or mitochondrial diseases (MD). The aim of this study is to describe the clinical, molecular, and histological characteristics of a consecutive cohort of patients with cardiomyopathy associated with NMDs or MDs referred to a tertiary cardiomyopathy clinic. Consecutive patients with a definitive diagnosis of NMDs and MDs presenting with a cardiomyopathy phenotype were described. Seven patients were identified: two patients with ACAD9 deficiency (Patient 1 carried the c.1240C>T (p.Arg414Cys) homozygous variant in ACAD9; Patient 2 carried the c.1240C>T (p.Arg414Cys) and the c.1646G>A (p.Ar549Gln) variants in ACAD9); two patients with MYH7-related myopathy (Patient 3 carried the c.1325G>A (p.Arg442His) variant in MYH7; Patient 4 carried the c.1357C>T (p.Arg453Cys) variant in MYH7); one patient with desminopathy (Patient 5 carried the c.46C>T (p.Arg16Cys) variant in DES); two patients with mitochondrial myopathy (Patient 6 carried the m.3243A>G variant in MT-TL1; Patient 7 carried the c.253G>A (p.Gly85Arg) and the c.1055C>T (p.Thr352Met) variants in MTO1). All patients underwent a comprehensive cardiovascular and neuromuscular evaluation, including muscle biopsy and genetic testing. This study described the clinical phenotype of rare NMDs and MDs presenting as cardiomyopathies. A multidisciplinary evaluation, combined with genetic testing, plays a main role in the diagnosis of these rare diseases, and provides information about clinical expectations, and guides management.

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies.

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.

Early Immunotherapy and Longer Corticosteroid Treatment Are Associated With Lower Risk of Relapsing Disease Course in Pediatric MOGAD.

BACKGROUND AND OBJECTIVES: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). METHODS: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up. RESULTS: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021). DISCUSSION: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).

Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey.

OBJECTIVE: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy. METHODS: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected. RESULTS: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%). DISCUSSION: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario.

Onasemnogene abeparvovec gene replacement therapy for the treatment of spinal muscular atrophy: a real-world observational study.

Spinal muscular atrophy (SMA) is a genetically inherited recessive neuromuscular disease that causes muscular atrophy and weakness. Onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) is a targeted therapy approved to treat patients with SMA in >40 countries worldwide. This study describes the clinical efficacy and tolerability of gene replacement therapy with onasemnogene abeparvovec over a 3-month period in 9 SMA type 1 patients aged 1.7-48 months, with 7 patients on stable nusinersen (i.e., had received all four nusinersen loading doses before inclusion in this study). Liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin), troponin I, platelet counts, creatinine levels, and motor function (CHOP-INTEND) were monitored. For the seven patients on stable nusinersen, the median baseline CHOP-INTEND score increased significantly during nusinersen treatment (Wilcoxon signed-rank test p = 0.018) and at 3 months after switching to onasemnogene abeparvovec (Wilcoxon signed-rank test p = 0.0467). We also identified two patients who responded poorly to nusinersen but showed the largest increase in baseline CHOP-INTEND scores at 1 and 3 months after switching, which could suggest that poor responders to nusinersen may respond favorably to onasemnogene abeparvovec. No unknown adverse events occurred. One patient developed moderate/severe thrombocytopenia 1 week after onasemnogene abeparvovec administration that resolved after treatment. Our study suggests the possibility of a change in the dynamic of CHOP-INTEND for patients who respond poorly to nusinersen after switching therapy to onasemnogene abeparvovec. Alternatively, patient age at treatment initiation may impact the response to onasemnogene abeparvovec. Testing in larger patient populations must be undertaken to assess the plausibility of these hypotheses.

Immediate and progressive neurological damage after electrical injury: A pediatric case report.

BACKGROUND: An electrical injury can cause multiple consequences, especially to the nervous system, both peripheral and central. Such consequences may present immediately as well as later on. AIMS OF THE STUDY: To report on a case of a 5-year-old boy with focal refractory status epilepticus after an electrical injury. METHODS: Clinical history, electroencephalography, neuroimaging, and laboratory data of a patient admitted to our emergency department. RESULTS: A 5-year-old male received an electrical shock by contact with an alternating current source after coming out of the pool. When reaching our emergency department, focal seizures was observed in the same site affected by the electrical insult, with progressive structural changes in the related brain area. In the days after, his neurological conditions dramatically evolved leading to brain death. CONCLUSIONS: Based on our knowledge, this is the first report on refractory status epilepticus in a child after electrical injury. The possible underlying pathogenetic mechanisms are not yet clear.

Malignant cerebral infarction associated with COVID-19 in a child.

Neurological manifestations, such as encephalitis, meningitis, ischemic, and hemorrhagic strokes, are reported with increasing frequency in patients affected by Coronavirus disease 2019 (COVID-19). In children, acute ischemic stroke is usually multifactorial: viral infection is an important precipitating factor for stroke. We present a case of a child with serological evidence of SARS-CoV-2 infection whose onset was a massive right cerebral artery ischemia that led to a malignant cerebral infarction. The patient underwent a life-saving decompressive hemicraniectomy, with good functional recovery, except for residual hemiplegia. During rehabilitation, the patient also developed a lower extremity peripheral nerve neuropathy, likely related to a long-Covid syndrome.

Spinal Nerve Roots Abnormalities on MRI in a Child with SURF1 Mitochondrial Disease.

Variants in SURF1, encoding an assembly factor of mitochondrial respiratory chain complex IV, cause Leigh syndrome (LS) and Charcot-Marie-Tooth type 4K in children and young adolescents. Magnetic resonance imaging (MRI) appearance of enlarged nerve roots with postcontrastographic enhancement is a distinctive feature of hypertrophic neuropathy caused by onion-bulb formation and it has rarely been described in mitochondrial diseases (MDs). Spinal nerve roots abnormalities on MRI are novel findings in LS associated with variants in SURF1. Here we report detailed neuroradiological and neurophysiologic findings in a child with LS and demyelinating neuropathy SURF1-related. Our case underlines the potential contributive role of spinal neuroimaging together with neurophysiological examination to identify the full spectrum of patterns in MDs. It remains to elucidate if these observations remain peculiar of SURF1 variants or potentially detectable in other MDs with peripheral nervous system involvement.

Atypical Clinical and Neuroradiological Findings in a Child With Bifacial Weakness With Paresthesias.

BACKGROUND: Guillain-Barré syndrome (GBS) is the broad term used to describe a number of related acute autoimmune neuropathies, which together form a continuous spectrum of variable and overlapping syndromes. Bifacial weakness with paresthesias (BFP) is a rare variant of GBS, characterized by isolated facial diplegia in the absence of ophthalmoplegia, ataxia, or limb weakness, and it is usually associated with distal limb paresthesias. CASE DESCRIPTION: An 8-year-old boy was brought to our attention; because 5 days before coming to the hospital, he noticed he could no longer smile. Bilateral facial droop and inability to close both eyes were evident along with slight paresthesias at the hands and feet and gait disturbances. He progressively developed hypophonia, dysarthria, dysphagia associated with dysmetria, and limb ataxia. Nerve conduction studies showed a demyelinating polyneuropathy. Brain and spine magnetic resonance imaging (MRI) revealed contrast enhancement of both facial nerves and cauda equina nerve roots along with a hyperintense signal of the periaqueductal gray matter, superior cerebellar peduncles, and pontine tegmentum. Because BFP is not typically associated with other cranial neuropathies or ataxia, these clinical features along with peculiar MRI findings supported the diagnosis of "BFP plus." Finally, it can be speculated that this case configures a rare overlap between BFP and the other GBS variants, such as Bickerstaff encephalitis. CONCLUSIONS: This atypical case underlines the potential role of MRI in contributing to refining the nosological classification of GBS spectrum and optimizing individual treatment, especially in children where unusual manifestations are not infrequent and neurological examination is more challenging.

Acute disseminated encephalomyelitis in a patient with Noonan syndrome: A rare autoinflammatory complication or coincidence?

We describe a 13-years-old girl, previously diagnosed with PTPN11-associated Noonan Syndrome (NS), who presented to the pediatric emergency department for fever and drowsiness, which gradually worsened within 48 h. On admission, brain magnetic resonance imaging (MRI) scan showed diffuse, symmetric, multiple, poorly demarcated, confluent hyperintense lesions on MRI T2w-images, located in the Central Nervous System (CNS). In the absence of a better explanation and according to the current diagnostic criteria, a diagnosis of Acute Disseminated Encephalomyelitis (ADEM) was performed. The patient was first treated with intravenous methylprednisolone, then with intravenous immunoglobulin (IVIG). Owing to the poor clinical response, three sessions of therapeutic plasma exchange (TPE) were finally performed, with a progressive improvement. Follow-up MRI performed after three months from the onset revealed a considerable reduction in brain lesions, while cervical and dorsal ones were substantially unmodified. Neurological examination showed a full recovery of cognitive function and improved strength and tone of the upper limbs, while tetrahyporeflexia and proximal weakness of lower limbs were still appreciable. To date, this is the first described case of ADEM occurring in a patient with NS.

A novel organ-chip system emulates three-dimensional architecture of the human epithelia and the mechanical forces acting on it.

Successful translation of in vivo experimental data to human patients is an unmet need and a bottleneck in the development of effective therapeutics. Organ-on-Chip technology aims to address this need by leveraging recent significant advancements in microfabrication and biomaterials, which enable modeling of organs and their functionality. These microengineered chips offer researchers the possibility to recreate critical elements of native tissue architecture such as in vivo relevant tissue-tissue interface, air-liquid interface, and mechanical forces, including mechanical stretch and fluidic shear stress, which are crucial to recapitulate tissue level functions. Here, we present the development of a new, comprehensive 3D cell-culture system, where we combined our proprietary Organ-Chip technology with the advantages offered by three-dimensional organotypic culture. Leveraging microfabrication techniques, we engineered a flexible chip that consists of a chamber containing an organotypic epithelium, surrounded by two vacuum channels that can be actuated to stretch the hydrogel throughout its thickness. Furthermore, the ceiling of this chamber is a removable lid with a built-in microchannel that can be perfused with liquid or air and removed as needed for direct access to the tissue. The bottom part of this chamber is made from a porous flexible membrane which allows diffusive mass transport to and from the microfluidic channel positioned below the membrane. This additional microfluidic channel can be coated with endothelial cells to emulate a blood vessel and recapitulate endothelial interactions. Our results show that the Open-Top Chip design successfully addresses common challenges associated with the Organs-on-Chip technology, including the capability to incorporate a tissue-specific extracellular matrix gel seeded with primary stromal cells, to reproduce the architectural complexity of tissues by micropatterning the gel, and to extract the gel for H&E staining. We also provide proof-of-concept data on the feasibility of using the system with primary human skin and alveolar epithelial cells.

Early treatment with Ataluren of a 2-year-old boy with nonsense mutation Duchenne dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by mutations, in most cases deletions and duplications, in the dystrophin gene. Point mutations account for 13% and stop codon mutations are even rarer. Ataluren was approved for the treatment of DMD caused by nonsense mutations in 2014, and several clinical trials documented its efficacy and safety. However, few real-life experience data is available, especially in pediatric age. We report the case of a 2-year- ambulant child affected by DMD caused by the stop-codon mutation c.10801C > T, p.Gln3601X in exon 76, who was early treated with Ataluren at a dosage of 40 mg/kg/die, and presented a rapid improvement in both muscle strength and cognitive and social skills.

Is Covid-19 lockdown related to an increase of accesses for seizures in the emergency department? An observational analysis of a paediatric cohort in the Southern Italy.

BACKGROUND: The World Health Organization (WHO) declared a global pandemic of Covid-19 on 11 March 2020. The lockdown caused a lifestyle changes: an increase in the use of mobile media devices (MMDs), sleep and psychiatric disorders, incorrect habits regarding food and physical activities. We investigate prevalence of admission for seizures at our emergency department (ED), during Italian lockdown, comparing with that of the same period of the previous year (2019), and the relationship with some lifestyle changes. METHODS: In this observational study, patients (4-14 years) with seizures that accessed at our ED, during Italian lockdown, were eligible. Non-epileptic events and febrile seizures were excluded. We describe two groups: patients with new-onset seizures and not. Moreover, a questionnaire concerning use of MMDs and sleep habits was administered. RESULTS: Fifty-seven patients were included; median age 8.03 years. Considering only paediatric medical emergencies, the prevalence of accesses for seizures was 2.6% (CI 95% 0.020-0.034), while the incidence was 0.94% (CI 95% 0.006-0.0149). There was a statistically significant difference with prevalence of previous years, χ2 102.21 (p = 0.0001). We also reported a difference in daily screen time (DST) (p = 0.001) and total sleep time (TST) (p = 0.045), in all population, between period pre- and during lockdown. A negative correlation between DST and seizures latency (Spearman's ρ -0.426, p = 0.038) was found. In the two groups, the results were partially overlapping. CONCLUSIONS: During lockdown period, we assisted to an increase of accesses for seizures. It is conceivable that a sleep time change and/or higher MMD use could act as triggers for seizures.