Evolution of neuropsychological and behavioral profile in a cohort of pediatric patients with Becker muscular dystrophy in a longitudinal study.

It has long been reported that neuropsychological deficits may be present in dystrophinopathies, specifically non-progressive cognitive impairment and a global deficit in executive functions; this neurocognitive profile has been less explored in patients with Becker than Duchenne muscular dystrophy (BMD/DMD). We conducted a longitudinal study to explore the evolution of neuropsychological and behavioural profile in a cohort of paediatric BMD. Seventeen patients with BMD without intellectual disability were assessed using a full battery of tests, including intellectual, adaptive and executive functioning, language and behavioral features. Tests were performed at baseline and after 12 months. The results showed adequate cognitive and adaptive profile with falls in Working Memory, as well as lower scores in executive functions. An improvement was observed in Processing Speed. Behavioral questionnaires confirmed a negative trend, while in normal ranges. We found a statistically significant difference between T0 and T1 in some items exploring executive functions. No statistically significant difference was observed stratifying patients by mutation site or IQ level. In conclusion, our study suggests that BMD patients have a stable neurocognitive profile, while a deflection in the executive functions may be observed. We recommend a careful monitoring to intercept learning disabilities and promptly start a multimodal rehabilitation.

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.

Digital health and Clinical Patient Management System (CPMS) platform utility for data sharing of neuromuscular patients: the Italian EURO-NMD experience.

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature.

Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients' characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.

Longitudinal Analysis of PUL 2.0 Domains in Ambulant and Non-Ambulant Duchenne Muscular Dystrophy Patients: How do they Change in Relation to Functional Ability?

BACKGROUND: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. METHODS: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. RESULTS: At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). CONCLUSION: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.

Type I spinal muscular atrophy patients treated with nusinersen: 4-year follow-up of motor, respiratory and bulbar function.

BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

Neurocognitive profile of a cohort of SMA type 1 pediatric patients and emotional aspects, resilience and coping strategies of their caregivers.

Spinal muscular atrophy (SMA) type 1 represents the most severe condition of the spectrum of SMA 5q. In the absence of therapeutic interventions, patients do not achieve any motor milestone and their life expectancy does not exceed two years of age. To date, three disease-modifying drugs have been approved for SMA type I. These treatments have radically changed the natural history of the disease, improving motor, respiratory and bulbar functions. In recent years huge amount of data have been collected worldwide related to motor, respiratory and swallowing function outcome in treated patients, whereas the neurocognitive profile of treated patients has been poorly explored. Here we report the neurocognitive development profile of a cohort of SMA type I children treated with a disease modifying therapy. We also describe the burden and resilience as well as the coping strategies of their caregivers. Our finding show a global developmental delay in most patients and defects in gross motor functions contribute most to lower the general development quotient of Griffiths III, whereas the scores obtained on evaluating learning and language abilities scales suggest a positive trend in the developmental trajectory of general neurocognitive abilities. Some parents reported anxiety and stress but overall they were resilient (and had good coping strategies towards the burden of care for their child. These results reinforce the importance of routinely assessing the neurocognitive aspects in SMA type I patients and to offer an early intervention to favor the psychosocial development of these children.

Long term follow-up of scoliosis progression in type II SMA patients.

The aim of this study is to retrospectively assess onset and progression of scoliosis in type II SMA patients not treated with the approved disease modifying treatments. Scoliosis was evaluated by measuring the scoliosis angle on X-ray obtained in the anteroposterior view in sitting position (Cobb's angle method). Eighty-four patients had at least one assessment of scoliosis angle (287 assessments). There was a positive correlation between age and scoliosis angles (p<0.001) with a progressive increase of scoliosis with age. When subdividing the population by HFMSE score (<10; 11-22;> 22), there was a progressive increase in scoliosis angles with decreasing HFMSE scores. The difference between HFMSE categories was significant (p<0.001). Fifty-four patients had at least two assessments at 6-month distance and were retained for the longitudinal analysis. Using a mixed model, age, functional status and scoliosis angle at baseline were predictive on scoliosis progression. The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74-6.52). Our results confirm the progression of scoliosis in untreated type II SMA providing details of the progression in relation to different variables. With different therapeutical options being available in many countries, our findings will provide reference data for establishing possible differences in the trajectories of progression with treated type II individuals.

Switching therapies: safety profile of Onasemnogene abeparvovec-xioi in a SMA1 patient previously treated with Risdiplam.

Three disease-modifying drugs (Nusinersen, Risdiplam and Onasemnogene abeparvovec) have been approved for SMA type I. Onasemnogene abeparvovec (GRT) can be administered in naïve patients or patients who are already being treated with Nusinersen or Risdiplam. Safety data on GRT in naïve patients or previously treated Nusinersen have been extensively described whereas any case of switch therapy from Risdiplam to GRT has been reported yet. We report on a SMA type I patient treated with Risdiplam by 2 months and switched to GRT at 5 months. She manifested the more common and awaited side effects that resolved in 3 months. The follow-up after 9 months from GRT infusion showed normal blood count, renal and cardiac function. She had great improvement in motor outcome, and no respiratory and bulbar problems as well as normal neurocognitive profile. This case suggests that the GRT may be safe also in patients previously treated with Risdiplam.

Neuropsychological and behavioral profile in a cohort of Becker muscular dystrophy pediatric patients.

Cognitive and executive function impairment as well as the association between executive functions and dystrophin gene mutation position have been widely investigated in individuals with Duchenne muscular dystrophy, whereas few studies explored these functions in Becker muscular dystrophy patients. The aim of this study is to investigate the neuropsychological and behavioral profile in a cohort of Becker muscular dystrophy patients and whether there is any correlation with site of dystrophin gene mutation. This is a single-center, observational, cross-sectional study in which a full neuropsychological assessment, including intellectual functioning, executive functions, and language abilities, was performed in children and adolescents without cognitive impairment. A comparison between groups based on site of mutation or Intelligence Quotient level was attempted. 22 patients were enrolled. Overall, the patients in our cohort did not perform well in tests investigating the executive functions. No statistically significant difference was found in groups stratified by site of mutation or cognitive level. This study confirms that these patients have a risk of impairment of the executive functions, despite having a normal Intelligence Quotient in most cases (mean 94). This is a very important aspect, as it puts them at risk of developing learning disabilities.

Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.

The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.

Age-related sensory neuropathy in patients with spinal muscular atrophy type 1.

INTRODUCTION/AIMS: Spinal muscular atrophy type 1 (SMA 1) is a devastating motor neuron disorder that leads to progressive muscle weakness, respiratory failure and premature death. Although sensory electrophysiological changes have been anecdotally found in pediatric SMA 1 patients, the age of onset of sensory neuropathy remains unknown. METHODS: Sensory nerve conduction studies of the median and sural nerves were performed in 28 consecutive SMA 1 patients of different ages. Sensory nerve conduction velocities and sensory nerve action potential (SNAP) amplitudes recorded in these patients were compared with those obtained from 93 healthy subjects stratified by age. RESULTS: SNAP amplitudes decreased with increasing age in the sural and median nerves, without any significant difference between upper and lower limbs. DISCUSSION: Our data suggest that sural and median nerve SNAP amplitudes are normal in younger patients, while an axonal neuropathy appears in older ones.

Expanded phenotype of AARS1-related white matter disease.

PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

Management of motor rehabilitation in individuals with muscular dystrophies. 1st Consensus Conference report from UILDM - Italian Muscular Dystrophy Association (Rome, January 25-26, 2019).

Muscular dystrophy (MD) is a group of neuromuscular diseases characterized by progressive muscle weakness due to various mutations in several genes involved in muscle structure and function. The age at onset, evolution and severity of the different forms of MD can vary and there is often impairment of motor function and activities of daily living. Although there have been important scientific advances with regard to pharmacological therapies for many forms of MD, rehabilitation management remains central to ensuring the patient's psychophysical well-being. Here we report the results of an Italian consensus conference promoted by UILDM (Unione Italiana Lotta alla Distrofia Muscolare, the Italian Muscular Dystrophy Association) in order to establish general indications and agreed protocols for motor rehabilitation of the different forms of MD.

Type I SMA "new natural history": long-term data in nusinersen-treated patients.

OBJECTIVE: The aim of this paper was to report the 2-year follow-up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. METHODS: Sixty-eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE-2) at the time they started treatment and 12 and 24 months after that. RESULTS: For both CHOP and HINE-2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24-month scores for the whole group. When age subgroups (<210 days, <2 years, 2-4 years, 5-11 years, 12-18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE-2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. INTERPRETATION: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

BACKGROUND: The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. METHODS: All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. RESULTS: The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. CONCLUSIONS: Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment.

Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen.

OBJECTIVE: To evaluate the effects of nusinersen on respiratory function of patients with type 1 spinal muscular atrophy. STUDY DESIGN: Observational, longitudinal cohort study. We collected respiratory data from 118 children with type 1 spinal muscular atrophy and differing pulmonary requirements and conducted a semistructured qualitative interview among a subsample of caregivers at baseline, 6 months, and 10 months after the first nusinersen treatment. Patients were stratified according to ventilation modalities and age at study entry. RESULTS: Most patients in our cohort remained stable (84/109 = 77%). More than 80% of the children treated before age 2 years survived, in contrast to the lower survival reported in natural history studies, and did so without tracheostomy or noninvasive ventilation (NIV) ≥16 hours. In those less than 2 years old, only 3 patients shifted from NIV ≤10 hours to NIV >10 hours, and the other 3 reduced the hours of NIV required. Most of the older patients remained stable; this included not only those on tracheostomy or NIV >10 hours but also 75% of those on NIV ≤10 hours. CONCLUSIONS: Our results suggest that nusinersen may produce some improvement in the progression of respiratory impairment, both in terms of survival and need for respiratory support ≥16 hours, especially before the age of 2 years.

Evaluation of gait in Duchenne Muscular Dystrophy: Relation of 3D gait analysis to clinical assessment.

Walking ability in Duchenne Muscular Dystrophy (DMD) deteriorates progressively until complete loss of the function. Interventions aimed at maintaining ambulatory ability relies on accurate clinical-based scores and evaluations of walking. This kind of assessment has intrinsic limitations. A 3D optoelectronic system could provide elements useful for the functional evaluation of patients with DMD. Nineteen boys with DMD were evaluated using the 6-Minutes Walking Test, North Star Ambulatory Assessment and 3D gait analysis. Participants' gait parameters were compared to those of an age-matched control group and correlated with standard clinical scores. Seventeen kinematic variables differed between DMD and control groups. Strong correlations with North Star Ambulatory Assessment were found for stride width, gait velocity and ankle angles on the sagittal plane. The 6-Minutes Walking test did not correlate with investigated kinematic variables but showed a correlation with North Star Ambulatory Assessment. Our data support the reported DMD gait pattern characterized by increased anterior pelvic tilt and ankle plantar flexion. The stride width and ankle kinematics emerged as the main representative gait parameters of DMD global ambulatory status. Although preliminary, our findings suggest that 3D gait analysis may provide useful objective and accurate parameters reflecting the functional ability of individuals with DMD.

'Amish Nemaline Myopathy' in 2 Italian siblings harbouring a novel homozygous mutation in Troponin-I gene.

Amish Nemaline Myopathy is a severe form of nemaline myopathy associated to mutation in TNNT1 gene, firstly reported among the Old Order Amish. Here we report two Italian siblings who manifested, by the age of 7 months, progressive and severe muscle weakness and wasting, respiratory insufficiency, pectus carinatum deformity and failure to thrive. Muscle biopsy was consistent with nemaline myopathy and novel homozygous missense mutation in TNNT1 was found. Our cases expand the mutational spectrum of TNNT1, confirm the invariable peculiar clinical phenotype also outside the Amish population, and suggest that TNNT1 should be considered for molecular analysis in NM patients with chest deformities and progressive contractures.