Changes in pNFH Levels in Cerebrospinal Fluid and Motor Evolution after the Loading Dose with Nusinersen in Different Types of Spinal Muscular Atrophy.

Aim and Objectives: The objective of our retrospective study was to investigate the changes in pNFH levels in cerebrospinal fluid, which is a reliable marker of neuronal damage, after the loading dose of nusinersen in different types of spinal muscular atrophy. Materials and Methods: We analyzed the spinal muscular atrophy types, the number of copies of the SMN2 gene, and the progression of the motor status using specific motor function scales in a group of 38 patients with spinal muscular atrophy types 1, 2, and 3. Results: We found a significant inverse correlation between pNFH levels and patient age, progress on functional motor scales, and nusinersen administration. Our results also revealed that the neurofilament levels in the cerebrospinal fluid were higher in patients with 2 SMN2 copies than those with more than 2 copies, although the association was not statistically significant due to the abnormal distribution of the values. Conclusions: We identified several predictors of favorable evolution under nusinersen treatment, including spinal muscular atrophy type 1, children aged ≤ 30 months, and the presence of only 2 copies of SMN2. Our study provides important insights into the use of pNFH as a biomarker to monitor disease progression and responses to treatment in patients with spinal muscular atrophy.

Clinical and Electrophysiological Changes in Pediatric Spinal Muscular Atrophy after 2 Years of Nusinersen Treatment.

In the new therapeutic era, disease-modifying treatment (nusinersen) has changed the natural evolution of spinal muscular atrophy (SMA), creating new phenotypes. The main purpose of the retrospective observational study was to explore changes in clinical evolution and electrophysiological data after 2 years of nusinersen treatment. We assessed distal compound motor action potential (CMAP) on the ulnar nerve and motor abilities in 34 SMA patients, aged between 1 and 16 years old, under nusinersen treatment, using specific motor scales for types 1, 2 and 3. The evaluations were performed at treatment initiation and 26 months later. There were registered increased values for CMAP amplitudes after 2 years of nusinersen, significantly correlated with motor function evolution in SMA type 1 patients (p < 0.005, r = 0.667). In total, 45% of non-sitters became sitters and 25% of sitters became walkers. For SMA types 1 and 2, the age at the treatment initialization is highly significant (p < 0.0001) and correlated with treatment yield. A strong negative correlation (r = −0.633) was observed for SMA type 1 and a very strong negative correlation (r = −0.813) for SMA type 2. In treated SMA cases, the distal amplitude of the CMAP and motor functional scales are important prognostic factors, and early diagnosis and treatment are essential for a better outcome.

Physical Therapy and Nusinersen Impact on Spinal Muscular Atrophy Rehabilitative Outcome.

INTRODUCTION: Spinal muscular atrophy (SMA) is a progressive neurological disease with autosomal recessive transmission that affects motor neurons, causing their loss and resulting in muscle waste and motor deficiency. Nusinersen, the first SMN2 pre-mRNA targeted therapy approved by the Food and Drug Administration and the European Medicines Agency, has demonstrated high efficacy in improving motor function, as well as respiratory and nutritional statuses. MATERIALS AND METHODS: We observed 55 patients (children/adolescents) diagnosed with spinal muscular atrophy (SMA), who received nusinersen therapy. To investigate the benefits of physical therapy on rehabilitation outcomes, we compared the motor evolution of patients who received nusinersen and performed daily physical therapy (study group) to those of the control group, who received only nusinersen therapy. RESULTS: Motor skill improvements were statistically significantly (p < 0.001) higher in the study group, being almost four times better (12.66%), effect size, in comparison to the control group (3.18%). CONCLUSIONS: Physical therapy has provided superior results for those who receive it on a regular basis. These results include the correction of posture, reduction in stiffness, expansion of the range of motion and strengthening of muscles, thus allowing patients to do more movements and boosting their ability to perform everyday tasks.

Comparative Analysis of the Quality of Life in Families with Children or Adolescents Having Congenital versus Acquired Neuropathology.

AIM: This research aims to determine whether the time of injury (congenital or acquired) affects the quality of life (QOL) in families having a child or adolescent with neurological impairment. DESIGN: Comparative, cross-sectional study. MATERIAL AND METHODS: To find out if there are differences in the quality of life domains between these two groups, 66 subjects (31 mothers of patients with congenital disorders and 35 mothers of patients with acquired disorders) completed the PedsQL-Family Impact Module (PedsQL-FIM), the World Health Organization Quality of Life Instrument-Short Form (WHOQOL-BRIEF), and the Cognitive Emotion Regulation Questionnaire (CERQ). RESULTS: Analyzing the PedsQL-FIM dimensions, we found significant differences between groups in terms of emotional functioning, communication, and worry, which favor the congenital group. There are no statistically significant differences between social functioning, cognitive functioning, and daily activities groups. No significant differences between groups when evaluating the WHOQOL-BRIEF's domains (physical health, psychological health, social relationships, environment) have been found. According to CERQ results, adaptive strategies had higher mean scores in the congenital than in the acquired group. The mean score for maladaptive strategies in the congenital group is higher than that in the acquired one, except for catastrophizing, which is higher for acquired. CONCLUSION: Our findings show that the mothers of patients with acquired neuropathology have a lower quality of life in the emotional functioning, communication, and worry domains.

Expanding the Clinical Phenotype of 19q Interstitial Deletions: A New Case with 19q13.32-q13.33 Deletion and Short Review of the Literature.

19q13 microdeletion syndrome is a very rare genetic disease characterized by pre- and postnatal growth retardation, intellectual disability, expressive language impairment, ectodermal dysplasia, and slender habitus. Since the description of the first case in 1998, less than 30 cases have been reported worldwide. This article aims to review the knowledge gathered so far on this subject and to present the case of a 10-year-old girl admitted to the National University Center for Children Neurorehabilitation "Dr. Nicolae Robanescu" in November of 2018 who presented a slender habitus, growth retardation, facial dysmorphism, skeletal abnormalities, and ectodermal dysplasia. Array-CGH analysis revealed a 1.53 Mb deletion in the 19q13.32-q13.33 region. MLPA for the FKRP gene revealed that the microdeletion was de novo. The patient's phenotype overlapped with the clinical features of 19q13 microdeletion syndrome. To our knowledge, this is the first case of 19q13 microdeletion syndrome to ever be reported in Romania. We believe our case presents additional features that have never been previously reported in this syndrome, namely, dilatation of the third ventricle and subependymal cyst, left iris coloboma, and tracheomalacia. Moreover, unlike the other 19q13 microdeletion cases that presented with dystonia, our patient also presented dystonia but, interestingly, without having haploinsufficiency of the KMT2B gene.

Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular progressive disease, characterized by decreased amounts of survival motor neuron (SMN) protein, due to an autosomal recessive genetic defect. Despite recent research, there is still no cure. Nusinersen, an antisense oligonucleotide acting on the SMN2 gene, is intrathecally administered all life long, while onasemnogene abeparvovec-xioi, a gene therapy, is administered intravenously only once. Both therapies have proven efficacy, with best outcomes obtained when administered presymptomatically. In recent years, disease-modifying therapies such as nusinersen and onasemnogene abeparvovec-xioi have changed the natural history of SMA. METHODS: We observed seven SMA type I patients, who received both therapies. We compared their motor function trajectories, ventilation hours and cough assist sessions to a control group of patients who received one therapy, in order to investigate whether combination therapy may be more effective than a single intervention alone. RESULTS: Patients who received both therapies, compared to the monotherapy cohort, had the same motor function trajectory. Moreover, it was observed that the evolution of motor function was better in the 6 months following the first therapy than in the first 6 months after adding the second treatment. CONCLUSIONS: Our results suggest that early treatment is more important than combined therapy.

Findings regarding emotion regulation strategies and quality of life's domains in families having children with spinal muscular atrophy.

The severity of motor impairment and the psycho-emotional and social consequences of spinal muscular atrophy (SMA) impact both children and their families, who must adapt using cognitive-emotional strategies. We aimed to determine whether the domains of quality of life and the consequent emotion regulation strategies could be related, and if so, to what quantitative, at a statistically significant level. This study was conducted at the Dr. N. Robanescu National Clinical Center of Neurorehabilitation for Children and included 33 mothers questioned using the PedsQL-Family Impact Module (PedsQL-FIM) and Cognitive Emotion Regulation Questionnaire (CERQ). Statistical analysis of PedsQL-FIM data showed high positive Spearman's rho correlations between communication and social functioning (p=0.719), daily activities and cognitive functioning (p=0.704), family relationships and daily activities (p=0.705). The analysis of the Spearman's rho correlation coefficients reflected some moderate positive correlations between CERQ subscales: self-blame and catastrophizing (p=0.577), acceptance and refocus on planning (p=0.577), acceptance and putting into perspective (p=0.532), refocus on planning and positive reappraisal (p=0.630), positive reappraisal and putting into perspective (p=0.609). Maladaptive strategies affect family relationships, cognitive and social functioning, emotional functioning, and communication inside the family. Positive correlations were found between the adaptive strategies (acceptance, refocus on planning, putting into perspective, positive reappraisal) in the participants within our study group, showing their interest in attitude changing and actively solving the family tasks related to children's illness.

Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency.

Spinal muscular atrophy (SMA) is a spectrum of genetically and clinically heterogeneous diseases leading to the progressive degeneration of peripheric motor neurons with subsequent muscle weakness and atrophy. More than 95% of the cases of SMA are represented by homozygous mutations of the SMN1 gene (5q-SMA). Because this disease represents the leading cause of death due to a genetic cause and due to the availability of genetic therapies which can now save the life of the patient and stop the progress of the disease, early diagnosis is crucial. This report presents the case of a 13-year-old patient admitted to our hospital in 2018 who presented a phenotype typical to 5q-SMA. Next-generation sequencing (NGS) and Sanger sequencing of the SMN1 gene were performed, and a negative result was obtained. Consequently, we continued testing using whole-exome sequencing and discovered three mutations in the ASAH1 gene (one pathogenic and two variants of uncertain significance). Pathogenic mutations in the ASAH1 gene are responsible for spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease, which overlapped with our patient's phenotype. Currently, there are 45 SMA cases caused by mutations in the ASAH1 gene reported worldwide; however, the present case is the first reported in Romania.

New VOUS in CASK Gene Correlating with the MICPCH Phenotype.

We present the case of a three-year-old girl with normal family history who was admitted to our hospital for medical recovery. The patient had microcephaly, pontocerebellar hypoplasia, slight facial dysmorphism, axial hypotonia, epileptic seizures, absent walking skills and severe speech delay. Genetic testing identified a heterozygous intronic variant in the CASK gene, namely CASK c.278 + 5G>A, which has never been reported in the medical literature or in other databases (gnomAD, ClinVar, HGMD). In mammals as well as more distant species, the G nucleotide is fully conserved at this position, suggesting it may not tolerate variation. In silico tools predict the substitution to be deleterious. Pathogenic mutations of these gene are responsible of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome, which overlaps completely with our patient's phenotype.

Reliability and sources of variability of 3D kinematics and electromyography measurements to assess newly-acquired gait in toddlers with typical development and unilateral cerebral palsy.

The aim was to 1) determine intersession and intertrial reliability and 2) assess three sources of variability (intersubject, intersession and intertrial) of lower limb kinematic and electromyographic (EMG) variables during gait in toddlers with typical development (TD) and unilateral cerebral palsy (UCP) (age <3 years, independent walking experience ≤6 months). Gait kinematics and surface EMG were recorded in 30 toddlers (19 TD and 11 UCP), during two, 3D-motion capture sessions. Standard error of measurement (SEM) between trials (gait cycles) of the same session and between sessions was calculated to assess reliability. Standard deviations (SD) between subjects, sessions and trials were calculated to estimate sources of variability. Sixty-four percent of kinematic SEM-values were acceptable (2°-5°). Frontal plane measurements were most reliable (SEM 2°-4.6°). In toddlers with UCP, EMG variables were most reliable for affected side, distal muscles. Intrinsic (intertrial and intersubject) variability was high, reflecting both motor immaturity and the high variability of toddler gait patterns. In toddlers with UCP, variability was amplified by motor impairment and delayed motor development. 3D gait analysis and surface EMG are partially reliable tools to study individual gait patterns in toddlers in clinical practice and research, although some variables must be interpreted with caution.

Characteristics of newly acquired gait in toddlers with unilateral cerebral palsy: Implications for early rehabilitation.

BACKGROUND: Knowledge of the characteristics of newly acquired gait in toddlers with cerebral palsy (CP) is limited. OBJECTIVES: This study compared gait characteristics (spatiotemporal parameters, kinematics and lower-limb muscle activation) within the first 6 months of independent walking in toddlers with unilateral cerebral palsy (UCP) and typically developing (TD) children. METHODS: The gait of 28 TD toddlers and 13 toddlers with UCP, all up to 3 years old with maximum walking experience of 6 months, was recorded by using a 3-D optoelectronic system and surface electromyography (EMG). Statistical parametric mapping was used to compare the kinematic parameters and EMG envelopes. Mann-Whitney U test was used to compare spatiotemporal parameters between groups. Principal component analysis was used to determine whether the main kinematic results were related to the clinical measures. RESULTS: Toddlers with UCP had bilateral modifications of the spatiotemporal parameters during gait as compared with TD toddlers and temporal asymmetry. The largest kinematic difference between the UCP and TD groups was external pelvic rotation on the affected side (13.3°). Foot progression angle was external during swing phase on the affected side. The groups did not differ in muscle activation for the set of muscles recorded. Pelvic rotation was not associated with any of the clinical measures on the affected or non-affected sides of toddlers with UCP. CONCLUSIONS: Alterations in kinematic gait parameters were mostly found at the pelvis in toddlers with UCP and newly acquired gait. At that age, the external pelvic rotation on the affected side is more likely due to primary motor control disorders than compensatory mechanisms. These findings suggest that early rehabilitation should focus on proximal motor control, balance and symmetry to optimize gait development from the early stages in children with UCP.

Endometrial stromal sarcoma in a 27-year-old woman. Case report and literature review.

Endometrial stromal tumors are very rare, representing approximately 0.2% of uterine malignancies, having an incidence of one to two from a million of women. The diagnosis cannot be established by imaging, it is histopathological only, often necessitate supplementary immunohistochemistry tests. We report the case of a 27-year-old woman who had an initial diagnosis, in another hospital, of uterine adenomyoma, established by dilatation and uterine curettage and then by subsequently histopathological exam. This diagnosis led to an initial non-oncological surgery, with interannexial total hysterectomy. The establishment of the final histopathological diagnosis of stromal endometrial sarcoma has led to a serious reassessment of the case. Making a review of the literature, we found very few cases of endometrial stromal sarcoma in young women less than 30 years old and we have not identified any clear strategy of treatment. However, from precautionary and considering that may be at risk, even with very few cases reported, the distance metastases can be present, sometimes at large intervals of time, we decided, for oncological safety, reintervention after one month. At the second surgery, it was practiced bilateral salpingo-ovarectomy, cardinal ligaments excision, partial omentectomy, bilateral pelvic lymphadenectomy extended lumbo-aortic and interaortico-cava, sampling biopsy from the inguinal femoral adenopathy and re-excision of the vaginal vault. The evolution was favorable, the patient being follow-up together with the oncologist specialist.