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Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was −0.67 (2.80), −1.15 (3.98), −1.46 (3.37) and −1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was −1.47 (3.73), −2.78 (5.86), −2.95 (4.56) and −4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p < 0.001), the shoulder (p = 0.01) and the elbow domain (p < 0.001), with patients amenable to skipping exon 44 having smaller changes compared to those amenable to skipping exon 53. There was no difference within ambulant or non-ambulant cohorts when subdivided by exon skip class for the total and subdomains score (p > 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients.

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

INTRODUCTION We aimed to investigate the correlation between body composition (BC) and spinal muscular atrophy (SMA)‐specific motor function assessments. METHODS Patients with SMA types I or II, aged 1 to 10 years, were recruited in this cross‐sectional study. The protocol included anthropometric measurements, and dual‐energy X‐ray absoprtiometry to assess fat mass (FM), lean mass (LM), fat‐free mass (FFM), FM and FFM indexes (FMI, FFMI), and motor function assessments (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale for SMAI, and Hammersmith Functional Motor Scale―Expanded for SMAII). DISCUSSION Eighty‐eight children were included. All had a higher FM percentage than reference values. Motor function was moderately correlated with body mass index (BMI), FFMI, and LMI in SMAI, and weakly correlated with FFMI, LMI, and LM:FM ratio in SMAII. DISCUSSION BC shows promise as a potential biomarker for SMA, but further studies are needed.

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.

With recent advances in the treatment of Spinal Muscular Atrophy (SMA), there is a strong need to increase knowledge on the involvement of organs and systems outside the central nervous system. We investigated bone metabolism, bone mineral density (BMD) and fractures, and their possible correlation with age and motor capacities. Thirty-two children with SMA (27 type 2, 5 type 3), mean age 40 ± 32.3 months, underwent two evaluations at an 18-month interval (V1 and V2). Twelve of these children also underwent a third evaluation at month 36 (V3). Diet, bone metabolism, BMD, X-rays, and motor function (by the Hammersmith Functional Motor Scale Expanded – HFMSE – and the Upper Limb Module – ULM) were assessed. At V1, 25-OH vitamin D3 (25OH D) therapy was started, and dietary calcium intake adjusted according to the recommended dietary allowance. Low 25OH D levels and asymptomatic vertebral fractures were mainly observed at V1. At all visits, bone resorption markers were higher than normal. At V2 and V3, decreased BMD was observed. Higher spine BMD values at follow-up were associated with HFMSE score >12 at baseline (p

Summary Background Body composition assessment is paramount for spinal muscular atrophy type I (SMA I) patients, as weight and BMI have proven to be misleading for these patients. Despite its importance, no disease-specific field method is currently available, and the assessment of body composition of SMA I patients requires reference methods available only in specialized settings. Objective To develop predictive fat mass equations for SMA I children based on simple measurements, and compare existing equations to the new disease-specific equations. Design Demographic, clinical and anthropometric data were examined as potential predictors of the best candidate response variable and non-linear relations were taken into account by transforming continuous predictors with restricted cubic splines. Alternative models were fitted including all the dimensions revealed by cluster analysis of the predictors. The best models were then internally validated, quantifying optimism of the obtained performance measures. The contribution of nusinersen treatment to the unexplained variability of the final models was also tested. Results A total of 153 SMA I patients were included in the study, as part of a longitudinal observational study in SMA children conducted at the International Center for the Assessment of Nutritional Status (ICANS), University of Milan. The sample equally represented both sexes (56% females) and a wide age range (from 3 months to 12 years, median 1.2 years). Four alternative models performed equally in predicting fat mass fraction (fat mass/body weight). The most convenient was selected and further presented. The selected model uses as predictors sex, age, calf circumference and the sum of triceps, suprailiac and calf skinfold thicknesses. The model showed high predictive ability (optimism corrected coefficient of determination, R2 = 0.72) and internal validation indicated little optimism both in performance measures and model calibration. The addition of nusinersen as a predictor variable did not improve the prediction. The disease-specific equation was more accurate than the available fat mass equations. Conclusions The developed prediction model allows the assessment of body composition in SMA I children with simple and widely available measures and with reasonable accuracy.

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. What this paper adds Brain involvement is under-investigated in spinal muscular atrophy (SMA) type 1. Neuropathological data suggest progressive brain involvement in severe forms of SMA. Impaired cognitive performances are reported in small groups with SMA type 1. Data on language in those with SMA type 1 are limited to parent reports and non-formal assessments.

Objective: To determine the efficacy and safety of risdiplam, a centrally and peripherally distributed oral SMN2 pre-mRNA splicing modifier, in infants with Type 1 spinal muscular atrophy (SMA) treated for 12 months during the confirmatory Part 2 of the FIREFISH study (NCT02913482). Design/Methods: FIREFISH is an ongoing, multicenter, open-label study of risdiplam in infants aged 1–7 months at enrollment with Type 1 SMA and two copies of the SMN2 gene. Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels (plus exploratory efficacy outcomes). The primary objective of confirmatory Part 2 (n=41) is to investigate the efficacy of risdiplam at the dose selected in Part 1. The primary efficacy endpoint is the proportion of infants sitting without support for 5 seconds after 12 months on treatment, as assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, 3rd edition. Secondary outcomes include the achievement of motor milestones and respiratory endpoints such as time to permanent ventilation and percentage of infants who achieve a reduction of ≥30° in phase angle from baseline at Month 12 (as measured by respiratory plethysmography). Results: The primary endpoint of FIREFISH Part 2 at 12 months was met (data-cut: 14th November 2019). We will report efficacy and safety data, including respiratory outcomes, from the confirmatory Part 2 of the FIREFISH study in participants who have received risdiplam treatment for a minimum of 12 months. Conclusions: FIREFISH Part 2 will provide important data on the efficacy and safety of risdiplam in infants with Type 1 SMA.

Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD).Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5years, estimated that forced vital capacity (FVC) declined yearly by −4.2%, forced expiratory volume in 1sec by −5.0%, and peak expiratory flow (PEF) by −2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately+15% across disease stages). Mutations situated 3’ of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately −6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.

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.

The huge contribution of advances in the pediatric neurosciences, improvements in clinical practice, and new therapeutic options, has led to the development of new models of treatment and rehabilitation for dystonia in the last decade. It is now generally agreed that a multidimensional therapeutic approach is needed for children with motor disorders, whose motor function-conceived as a complex perceptive, motor and cognitive process - is impaired at a crucial time in their development, with a fall out on how their various adaptive functions evolve. Neurophysiological studies, modern neuroimaging techniques, and advances in cognitive psychology have all contributed to improving our understanding of the potential effects of treatments in early age - not only on the symptoms, but also on plasticity processes and neuronal reorganization. The International Classification of Functioning, Disability and Health (ICF) promoted by the WHO, and the diffusion of family-centered models of healthcare have underscored the importance of the ecological perspective with a view to providing effective therapies and a satisfactory quality of life for dystonic children and their families. The advances made in this area have made it necessary to study and develope more appropriate treatment outcome measures. In the light of these aspects, there is still not enough literature on the generally-accepted, exhaustive dystonia assessment tools. Given these limits, it might be useful to discuss the strengths and weaknesses of the main tools currently used in this setting.

Background Knowledge on resting energy expenditure (REE) in spinal muscular atrophy type I (SMAI) is still limited. The lack of a population-specific REE equation has led to poor nutritional support and impairment of nutritional status. Objective To identify the best predictors of measured REE (mREE) among simple bedside parameters, to include these predictors in population-specific equations, and to compare such models with the common predictive equations. Methods Demographic, clinical, anthropometric, and treatment variables were examined as potential predictors of mREE by indirect calorimetry (IC) in 122 SMAI children consecutively enrolled in an ongoing longitudinal observational study. Parameters predicting REE were identified, and prespecified linear regression models adjusted for nusinersen treatment (discrete: 0 = no; 1 = yes) were used to develop predictive equations, separately in spontaneously breathing and mechanically ventilated patients. Results In naive patients, the median (25th, 75th percentile) mREE was 480 (412, 575) compared with 394 (281, 554) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.009).In nusinersen-treated patients, the median (25th, 75th percentile) mREE was 609 (592, 702) compared with 639 (479, 723) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.949).Both in spontaneously breathing and mechanically ventilated patients, the best prediction of REE was obtained from 3 models, all using as predictors: 1 body size related measurement and nusinersen treatment status. Nusinersen treatment was correlated with higher REE both in spontaneously breathing and mechanically ventilated patients. The population-specific equations showed a lower interindividual variability of the bias than the other equation tested, however, they showed a high root mean squared error. Conclusions We demonstrated that ventilatory status, nusinersen treatment, demographic, and anthropometric characteristics determine energy requirements in SMAI. Our SMAI-specific equations include variables available in clinical practice and were generally more accurate than previously published equations. At the individual level, however, IC is strongly recommended for assessing energy requirements. Further research is needed to externally validate these predictive equations.

NKX2-1 mutations have been usually associated with a non-progressive neurological disease. Recent reports revealed a vast variability regarding its clinical expressivity. Aim of this work was widening the Benign Hereditary Chorea neurological, cognitive and behavioral phenotype through the description of a child and her family pedigree. Molecular analysis focused on NKX2-1 gene revealed a novel frameshift mutation in the three-generation members described. Cognitive scales detected a relevant developmental delay, and the clinical observation and Autism Diagnostic Observation Schedule -2 administration allowed the diagnosis of autism spectrum disorder in the proband. Microarray testing, further executed to exclude a double hit contextually provoking the complex neurodevelopmental disorder, revealed the 22q11.2 Duplication Syndrome. This paper may contribute to enlarge Benign Hereditary Chorea variable expressivity and, together with other studies reported in the literature, underlines the need to reconsider the term “benign,” verifying the opportunity of more a complex diagnosis.

We describe the clinical findings and MRI features observed in a child who presented a two-step disease course: he was hypotonic at birth and soon afterwards developed seizures, which were partially responsive to treatment; he subsequently showed developmental delay and a progressive neurological deterioration with the onset of severe seizures at around three years of age. Head MRI at age 20 days was unremarkable, whereas at 25 months it showed bilateral hyperintensity of the deep cerebellar nuclei; five months later, the signal hyperintensity was also present in the cerebellar white matter and ventral pontine fibre tracts. Molecular analysis revealed a novel ACOX1 mutation, predicting a largely truncated protein. The white matter involvement, which followed an ascending trajectory from cerebellar and brainstem structures to the cerebral hemispheres, seemed to originate from the perinuclear white matter of the deep cerebellar nuclei.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza&reg, ) enhances SMN2 gene expression. SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases. They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers. Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been investigated yet. Here, we analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the Hammersmith Functional Motor Scale Expanded (HFMSE). Our results demonstrate that myomiR serological levels decrease over disease course upon nusinersen treatment. Notably, miR-133a reduction predicted patients&rsquo, response to therapy. Our findings identify myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients.

Aim To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). Method A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov. Results Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP. Interpretation This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double-blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health. What this paper adds Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials.

Poretti-Boltshauser syndrome (PBS) is a recently described cerebellar disorder characterized by cerebellar dysplasia with cysts and an enlarged and square-like shaped fourth ventricle.1 The clinical phenotype includes nonprogressive cerebellar ataxia, ocular motor apraxia (OMA), intellectual disability, and frequent high myopia or retinal dystrophy.1 Mutations in LAMA1 have been identified as the cause of PBS.2

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).