Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review

Aim: To summarize the current knowledge on brain involvement in spinal muscular atrophy (SMA) type 1, focusing on brain pathology, cognition, and speech/language development. / Method: A scoping review was performed using the methodology of the Joanna Briggs Institute. Five databases and references from relevant articles were searched up to December 2019. Articles were screened on the basis of titles and abstracts. Full‐text papers published in peer‐reviewed journals in English were selected. / Results: Nineteen articles met eligibility criteria. Eight case series/reports on brain pathology showed abnormalities in few SMA type 0/1 cases, supported by findings in three post‐mortem examinations in mice. Four studies (three case–control, one cross‐sectional) on cognition reported contradictory results, with impaired cognitive performances in recent, small groups with SMA type 1. Four studies (three cross‐sectional, one observational) on speech/language showed that untreated SMA type 1 patients rarely achieve functional and intelligible speech, with data limited to parent reports/non‐formal evaluations. / Interpretation: Brain involvement is an under‐investigated aspect of SMA type 1, requiring further exploration in longitudinal studies. A deeper knowledge of brain involvement would improve the interpretation of clinical phenotypes and the personalization of rehabilitation programmes supporting patients' autonomies and quality of life. Additionally, it may help to define further outcome measures testing the efficacy of current and new developing drugs on this domain

Lessons Learned From Translational Research in Neuromuscular Diseases: Impact on Study Design, Outcome Measures and Managing Expectation

Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), two of the most common, child onset, rare neuromuscular disorders, present a case study for the translation of preclinical research into clinical work. Over the past decade, well-designed clinical trials and innovative methods have led to the approval of several novel therapies for SMA and DMD, with many more in the pipeline. This review discusses several features that must be considered during trial design for neuromuscular diseases, as well as other rare diseases, to maximise the possibility of trial success using historic examples. These features include well-defined inclusion criteria, matching criteria, alternatives to placebo-controlled trials and the selection of trial endpoints. These features will be particularly important in the coming years as the investigation into innovative therapy approaches for neuromuscular diseases continues

Spontaneous breathing pattern as respiratory functional outcome in children with spinal muscular atrophy (SMA)

Introduction: SMA is characterised by progressive motor and respiratory muscle weakness. We aimed to verify if in SMA children 1)each form is characterized by specific ventilatory and thoracoabdominal pattern(VTAp) during quiet breathing(QB); 2)VTAp is affected by salbutamol therapy, currently suggested as standard treatment, or by the natural history(NH) of SMA; 3)the severity of global motor impairment linearly correlates with VTAp. Materials and methods: VTAp was analysed on 32 SMA type I (SMA1, the most severe form), 51 type II (SMA2, the moderate), 8 type III (SMA3, the mildest) and 20 healthy (HC) using opto-electronic plethysmography. Spirometry, cough and motor function were measured in a subgroup of patients. Results: In SMA1, a normal ventilation is obtained in supine position by rapid and shallow breathing with paradoxical ribcage motion. In SMA2, ventilation is within a normal range in seated position due to an increased respiratory rate(p0.05) while tachypnea occurred in type I NH. A linear correlation(p<0.001) was found between motor function scales and VTAp. Conclusion: A negative or reduced %ΔVRC,P, indicative of ribcage muscle weakness, is a distinctive feature of SMA1 and SMA2 since infancy. Its quantitative assessment represents a non-invasive, non-volitional index that can be obtained in all children, even uncollaborative, and provides useful information on the action of ribcage muscles that are known to be affected by the disease. Low values of motor function scales indicate impairment of motor but also of respiratory function

Intellectual abilities, language comprehension, speech, and motor function in children with spinal muscular atrophy type 1

Background: Spinal muscular atrophy (SMA) is a chronic, neuromuscular disease characterized by degeneration of spinal cord motor neurons, resulting in progressive muscular atrophy and weakness. SMA1 is the most severe form characterized by significant bulbar, respiratory, and motor dysfunction. SMA1 prevents children from speaking a clearly understandable and fluent language, with their communication being mainly characterized by eye movements, guttural sounds, and anarthria (type 1a); severe dysarthria (type 1b); and nasal voice and dyslalia (type 1c). The aim of this study was to analyze for the first time cognitive functions, language comprehension, and speech in natural history SMA1 children according to age and subtypes, to develop cognitive and language benchmarks that provide outcomes for the clinical medication trials that are changing SMA1 course/trajectory. Methods: This is a retrospective study including 22 children with SMA1 (10 affected by subtype 1a-1b: AB and 12 by 1c: C) aged 3–11 years in clinical stable condition with a coded way to communicate “yes” and “no”. Data from the following assessments have been retrieved from patient charts: one-dimensional Raven test (RCPM), to evaluate cognitive development (IQ); ALS Severity Score (ALSSS) to evaluate speech disturbances; Brown Bellugy modified for Italian standards (TCGB) to evaluate language comprehension; and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) to assess motor functioning. Results: SMA 1AB and 1C children were similar in age, with the former characterized by lower CHOP-INTEND scores compared to the latter. All 22 children had collaborated to RCPM and their median IQ was 120 with no difference (p = 0.945) between AB and C. Global median score of the speech domain of the ALSSS was 5; however, it was 2 in AB children, being significantly lower than C (6.5, p < 0.001). TCGB test had been completed by 13 children, with morphosyntactic comprehension being in the normal range (50). Although ALSSS did not correlate with both IQ and TCGB, it had a strong (p < 0.001) correlation with CHOP-INTEND described by an exponential rise to maximum. Conclusions: Although speech and motor function were severely compromised, children with SMA1 showed general intelligence and language comprehension in the normal range. Speech impairment was strictly related to global motor impairment

Motor learning in unilateral cerebral palsy and the influence of corticospinal tract reorganization

Cerebral Palsy (CP) is a complex neurological disorder, characterized by congenital motor disability associated with behaviour, perception and cognition disorders. The sensorimotor impairments represent the main hallmark of the disease, significantly impacting the quality of life. So far, few studies have investigated motor learning abilities in CP and their association with the plastic reorganization of the motor system remains largely unknown. The present proof-of-principle study explored explicit motor sequence learning in children with unilateral CP and different patterns of motor system reorganization (bilateral, ipsilateral, contralateral). Children with unilateral CP, and a group of age-matched typically developing (TD) children, underwent a sequential finger tapping task, performed with the affected hand by children with CP and with the non-dominant hand by TD children. The pattern of corticospinal tract projections in hemiparetic patients was assessed by single-pulse Transcranial Magnetic Stimulation (TMS). Results showed the presence of finger dexterity impairments in children with unilateral CP presenting with a bilateral or an ipsilateral control of the affected (trained) hand, as compared to TD children. Conversely, motor sequence learning was impaired in unilateral CP with ipsilateral or contralateral corticospinal reorganization, but not in the case of a bilateral control of the paretic hand. These preliminary findings, although referred to small clinical samples, suggest that unilateral control of the paretic upper-limb, from the ipsilateral or the contralateral motor cortex, may not be sufficient to develop typical motor learning with the affected hand, which seems to require a bilateral representation in the motor cortex. This evidence has potential implications for fine motor skills rehabilitation in CP

Low-Intensity Vibration Protects the Weight-Bearing Skeleton and Suppresses Fracture Incidence in Boys With Duchenne Muscular Dystrophy: A Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

The ability of low-intensity vibration (LIV) to combat skeletal decline in Duchenne Muscular Dystrophy (DMD) was evaluated in a randomized controlled trial. Twenty DMD boys were enrolled, all ambulant and treated with glucocorticoids (mean age 7.6, height-adjusted Z-scores [HAZ] of hip bone mineral density [BMD] −2.3). Ten DMD boys were assigned to stand for 10 min/d on an active LIV platform (0.4 g at 30 Hz), while 10 stood on a placebo device. Baseline and 14-month bone mineral content (BMC) and BMD of spine, hip, and total body were measured with DXA, and trabecular bone density (TBD) of tibia with quantitative computed tomography (QCT). All children tolerated the LIV intervention well, with daily compliance averaging 78%. At 14 months, TBD in the proximal and distal tibia remained unchanged in placebo subjects (−1.0% and −0.2%), while rising 3.5% and 4.6% in LIV subjects. HAZ for hip BMD and BMC in the placebo group declined 22% and 13%, respectively, contrasting with no change from baseline (0.9% and 1.4%) in the LIV group. Fat mass in the leg increased 32% in the placebo group, contrasting with 21% in LIV subjects. Across the 14-month study, there were four incident fractures in three placebo patients (30%), with no new fractures identified in LIV subjects. Despite these encouraging results, a major limitation of the study is—despite randomized enrollment—that there was a significant difference in age between the two cohorts, with the LIV group being 2.8y older, and thus at greater severity of disease. In sum, these data suggest that noninvasive LIV can help protect the skeleton of DMD children against the disease progression, the consequences of diminished load bearing, and the complications of chronic steroid use. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research

NEDDylated Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors

DNA topoisomerase 1 (TOP11) inhibitors are mainstays of anticancer therapy. These drugs trap TOP1 on DNA, stabilizing the TOP1-cleavage complex (TOP1-cc). The accumulation of TOP1-ccs perturbs DNA replication fork progression, leading to DNA breaks and cell death. By analyzing the genomic occupancy and activity of TOP1, we show that cells adapt to treatment with multiple doses of TOP1 inhibitor by promoting the degradation of TOP1-ccs, allowing cells to better tolerate subsequent doses of TOP1 inhibitor. The E3-RING Cullin 3 ligase in complex with the BTBD1 and BTBD2 adaptor proteins promotes TOP1-cc ubiquitination and subsequent proteasomal degradation. NEDDylation of Cullin 3 activates this pathway, and inhibition of protein NEDDylation or depletion of Cullin 3 sensitizes cancer cells to TOP1 inhibitors. Collectively, our data uncover a previously unidentified NEDD8-Cullin 3 pathway involved in the adaptive response to TOP1 inhibitors, which can be targeted to improve the efficacy of TOP1 drugs in cancer therapy