Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

OBJECTIVE: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. METHODS: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). RESULTS: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). INTERPRETATION: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126-1135.

Early treatment of type II SMA slows rate of progression of scoliosis.

BACKGROUND: Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients. METHODS: Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance. RESULTS: There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016). CONCLUSION: This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.

Early neurological signs in infants identified through neonatal screening for SMA: do they predict outcome?

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months.  Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: • There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. • The proposed nosology describes a clinically silent disease, an intermediate category ('paucisymptomatic') and 'symptomatic SMA'. What is New: • The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. • The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.

Assessing Prevalence and Characteristics of Oro-bulbar Involvement in Children and Adults with SMA Type 2 and 3 Using a Multimodal Approach.

Bulbar and jaw muscles are impaired in patients with Spinal Muscular Atrophy (SMA) but the assessment of their severity and progression are limited by the lack of age-appropriate and disease-specific measures. We investigated mastication and swallowing in children and adults with SMA, sitters and walkers. In a 2-year multicentre cross-sectional prospective study, lip and tongue strength (Iowa Oral Performance Instrument), chewing and swallowing (Test of Masticating and Swallowing Solids), active mouth opening (aMMO) were compared to age-appropriate normative data. The perceived burden of oro-bulbar involvement (SMA-Health Index) was recorded. 78 patients were included, 45 children (median age 7.4 years),22 adults (median age 26.8 years) on nusinersen and 11 untreated (median age 32.7 years). Forty-three percent children had reduced mouth opening, 50% had prolonged total time to eat. These issues were more prominent in sitters than in walkers (p = 0.019, p = 0.014). Sixty-six percent needed increased swallows for bolus clearance. Nusinersen treated adults had median aMMO, tongue strength and total time at TOMASS values within normal range (z score: -1.40, -1.22, -1.32, respectively) whereas untreated adults had reduced aMMO (z score: -2.68) and tongue strength (z score: -2.20). Only a minority of children (2/17) and treated adults (5/21) reported burden in swallowing or mastication compared to all untreated adults (5/5). After 16 months, mastication and swallowing were stable in treated children and adults, whether sitters or walkers. The reported multimodal approach to assess oro-bulbar functions demonstrate that swallowing and mastication are impaired in SMA despite patients' perception. These results suggest a trend towards stabilization of oro-bulbar function in patients on long-term treatment with nusinersen.

GRN-/- iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis.

Heterozygous mutations in the gene coding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) while homozygous mutations are linked to neuronal ceroidolipofuscinosis (NCL). While both FTLD/NCL pathological hallmarks were mostly investigated in heterozygous GRN+/- brain tissue or induced pluripotent stem cell (iPSC)-derived neurons, data from homozygous GRN-/- condition are scarce, being limited to a postmortem brain tissue from a single case. Indeed, homozygous GRN-/- is an extremely rare condition reported in very few cases. Our aim was to investigate pathological phenotypes associated with FTLD and NCL in iPSC-derived cortical neurons from a GRN-/- patient affected by NCL. iPSCs were generated from peripheral blood of a GRN wt healthy donor and a GRN-/- patient and subsequently differentiated into cortical neurons. Several pathological changes were investigated, by means of immunocytochemical, biochemical and ultrastructural analyses. GRN-/- patient-derived cortical neurons displayed both TDP-43 and phospho-TDP-43 mislocalization, enlarged autofluorescent lysosomes and electron-dense vesicles containing storage material with granular, curvilinear and fingerprints profiles. In addition, different patterns in the expression of TDP-43, caspase 3 and cleaved caspase 3 were observed by biochemical analysis at different time points of cortical differentiation. At variance with previous findings, the present data highlight the existence of both FTLD- and NCL-linked pathological features in GRN-/- iPSC-derived cortical neurons from a NCL patient. They also suggest an evolution in the appearance of these features: firstly, FTLD-related TDP-43 alterations and initial NCL storage materials were detected; afterwards, mainly well-shaped NCL storage materials were present, while some FTLD features were not observed anymore.

Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening.

The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs. CONCLUSIONS: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. WHAT IS KNOWN: • The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease. • The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period. WHAT IS NEW: • Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients. • Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration.

Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10-12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (-5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.

Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.

Longitudinal Cognitive Assessment in Low-Risk Very Preterm Infants.

Background and Objectives: Preterm infants are at higher risk of neurodevelopmental impairment both at preschool and school ages, even in the absence of major neurological deficits. The early identification of children at risk is essential for early intervention with rehabilitation to optimize potential outcomes during school years. The aim of our study is to assess cognitive outcomes at preschool age in a cohort of low-risk very preterm infants, previously studied at 12 and 24 months using the Griffiths scales. Materials and Methods: Sixty-six low-risk very preterm infants born at a gestational age of <32 weeks were assessed at 12 and 24 months corrected age using the Griffiths Mental Development Scales (second edition) and at preschool age with the Wechsler Preschool and Primary Scales of Intelligence (third edition) (WPPSI-III). Results: At 12 and 24 months and at preschool age, low-risk very preterm infants showed scores within normal ranges with similar scores in males and females. A statistically significant correlation was observed in the general developmental quotient between 12 and 24 months; a further significant correlation was observed between the early cognitive assessments and those performed at preschool age, with a better correlation using the assessments at 24 months. Conclusion: The present study showed a favourable trajectory of cognitive development in low-risk very preterm infants, from 12 months to preschool age.

Singular cases of Alzheimer's disease disclose new and old genetic "acquaintances".

BACKGROUND: Alzheimer's disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age. OBJECTIVES: To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants. METHODS: Biomarkers of amyloid-ß deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS). RESULTS: We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases. CONCLUSIONS: This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.

Early Neurological Assessment and Long-Term Neuromotor Outcomes in Late Preterm Infants: A Critical Review.

Background and Objectives: Late preterm (LP) infants (born between 34 and 36 weeks of gestational age) are considered at higher risk of neonatal morbidities, mortality, and neurological impairments than full-term born infants (FT). The aim of this study was to provide a critical review of the literature outlining the different aspects of neurological function reported both in the neonatal period and in the follow up of late preterm infants. Materials and Methods: A comprehensive search of the MEDLINE, Embase, PsycINFO, and CINAHL electronic databases was made, using the following search terms: 'Late preterm infants', 'Near term infants', 'neurological assessment', 'neurological outcome', 'neuromotor outcome', cerebral palsy', 'CP', 'motor impairment', including all the studies reporting clinical neurological assessment of LP (including both neonatal period and subsequent ages). Results: A total of 35 articles, comprising 301,495 children, were included as fulfilling the inclusion criteria: ten reported neonatal neurological findings, seven reported data about the first two years after birth, eighteen reported data about incidence of CP and motor disorder during the infancy. Results showed a more immature neurological profile, explored with structured neurological assessments, in LP infants compared with FT infants. The LP population also had a higher risk of developing cerebral palsy, motor delay, and coordination disorder. Conclusion: LP had a higher risk of neurological impairments than FT infants, due to a brain immaturity and an increased vulnerability to injury, as the last weeks of gestational age are crucial for the development of the brain.

Can the CHOP-INTEND be used as An Outcome Measure in the First Months of Age? Implications for Clinical Trials and Real World Data.

BACKGROUND: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. OBJECTIVE: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. METHODS: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. RESULTS: our study includes 61 assessments collected < 2 weeks, 25 at 2-4 weeks, 20 at 5-8 weeks, 25 at 9-12 weeks and 20 at 13-17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. CONCLUSIONS: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects.

Communicative development inventory in type 1 and presymptomatic infants with spinal muscular atrophy: a cohort study.

OBJECTIVE: The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). METHODS: Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. RESULTS: The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. CONCLUSIONS: These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.

Gain and loss of upper limb abilities in Duchenne muscular dystrophy patients: A 24-month study.

Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by muscle weakness. The Performance of upper limb (PUL) test is designed to evaluate upper limb function in DMD patients across three domains. The aim of this study is to identify frequently lost or gained PUL 2.0 abilities at distinct functional stages in DMD patients. This retrospective study analyzed prospectively collected data on 24-month PUL 2.0 changes related to ambulatory function. Ambulant patients were categorized based on initial 6MWT distance, non-ambulant patients by time since ambulation loss. Each PUL 2.0 item was classified as shift up, no change, or shift down. The study's cohort incuded 274 patients, with 626 paired evaluations at the 24-month mark. Among these, 55.1 % had activity loss, while 29.1 % had gains. Ambulant patients showed the lowest loss rates, mainly in the shoulder domain. The highest loss rate was in the shoulder domain in the transitioning subgroup and in elbow and distal domains in the non-ambulant patients. Younger ambulant patients demonstrated multiple gains, whereas in the other functional subgroups there were fewer gains, mostly tied to singular activities. Our findings highlight divergent upper limb domain progression, partly linked to functional status and baseline function.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

Efficacy of Subchondroplasty in the Treatment of Pain Associated With Bone Marrow Lesions in the Osteoarthritic Knee.

Background: Bone marrow lesions (BMLs) are common subchondral defects revealed by magnetic resonance imaging (MRI) in patients with osteoarthritis, often associated with pain and functional limitation. Subchondroplasty (SCP) is a relatively new technique in which bone substitute material (BSM) is injected inside BML areas to provide structural support to the subchondral bone, preventing its collapse and reducing pain. Purpose/Hypothesis: The purpose of this study was to characterize changes in pain, functional and radiological outcomes, conversion to knee replacement, and complications after SCP. We hypothesized that ≥70% of patients would achieve a reduction in pain of ≥4 points on a numeric rating scale (NRS) at a 6-month follow-up after SCP. Study Design: Case series; Level of evidence, 4. Methods: Patients with symptomatic knee BMLs who underwent SCP were prospectively evaluated preoperatively and at 1, 6, 12, and 24 months postoperatively. Functional outcomes were measured with the NRS for pain, Knee Society Score (KSS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores. Radiographs and MRI were performed preoperatively and at 6- and 12-month follow-ups to verify edema healing and changes in bone structure. Results: A total of 50 patients were included in the study. The mean follow-up was 26 months (24-30 months). Compared with preoperative values, the mean NRS score decreased at every follow-up point (P < .0001 for all) and the IKDC, WOMAC, and KSS scores improved significantly at 6- and 12-month follow-ups. At 6 months postoperatively, 27 patients (54%) registered a reduction on the NRS of ≥4 points. Postoperative MRI revealed a hypointense zone surrounded by a hyperintense signal at the injection site. Standard radiography showed osteoarthritis grade worsening in 4 (8%) patients. Knee replacement was performed in 11 patients -in 7 patients due to the worsening or persistence of disabling symptoms and in 4 patients due to the progression of osteoarthritis. The leakage of BSM occurred in 6 patients without any clinical consequences during the study period. Conclusion: About half of the study patients achieved a reduction in the NRS of 4 points at the 6-month follow-up after SCP. Registration: NCT04905394 (ClinicalTrials.gov identifier).

A Longitudinal Follow-Up Study of Intellectual Function in Duchenne Muscular Dystrophy over Age: Is It Really Stable?

The aim of the study was to retrospectively evaluate the consistency of longitudinal findings on intellectual functioning in DMD boys and their relationship to behavioral and neuropsychiatric difficulties. The cohort included 70 patients of age 3 to 17 years with at least two assessments using the Wechsler scales. CBCL and clinical observation of behavior were also performed. Changes in total intelligence quotient were interpreted as stable or not stable using the reliable-change method. On the first assessment 43/70 had normal quotients, 18 borderline, 5 mild, and 4 moderate intellectual disability, while 27/70 had no behavioral disorders, 17 had abnormal CBCL, and 26 patients had clear signs of attention deficits despite normal CBCL. The remaining seven were untestable. The mean total intelligence quotient change in the cohort was -2.99 points (SD: 12.29). Stable results on TIQ were found in 63% of the paired assessments. A third of the consecutive cognitive assessments showed a difference of more than 11 points with changes up to 42 points. Boys with no behavioral/attention disorder had smaller changes than those with attention (p = 0.007) and behavioral disorders (p = 0.002). Changes in IQ may occur in Duchenne and are likely to be associated with behavioral or attention deficits.

Patient reported outcome measure for upper limb in Duchenne muscular dystrophy: correlation with PUL2.0.

The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement.

Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?

There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5-17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.

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.