Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.

BACKGROUND: Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases. CASE PRESENTATION: In the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father. CONCLUSIONS: Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

Old measures and new scores in spinal muscular atrophy patients.

INTRODUCTION: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale-Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items. METHODS: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients. RESULTS: The mean 12-month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar. CONCLUSIONS: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items.

Heart rate variability alterations in Dravet Syndrome: The role of status epilepticus and a possible association with mortality risk.

PURPOSE: Preliminary data suggest that patients with Dravet Syndrome (DS) have a reduced heart rate variability (HRV). This seems particularly evident in patients who experienced sudden unexpected death in epilepsy (SUDEP). This study aims at confirming these findings in a larger cohort and at defining clinical, genetic or electroencephalographic predictors of HRV impairment in DS patients. METHODS: DS patients followed at our Institution performed a 24h-ECG Holter to derive HRV parameters. We used as control population patients with epilepsy (PWEs) and healthy controls (HCs). In DS patients, we assessed the impact of different clinical, neurophysiological and genetic features on HRV alterations through multiple linear regression. After a mean follow-up of 7.4 ± 3.2 years since the HRV assessment, all DS patients were contacted to record death or life-threatening events. RESULTS: 56 DS patients had a significantly reduced HRV compared to both HCs and PWEs. A recent history of status epilepticus (SE) was the only significant predictor of lower HRV in the multivariate analysis. At follow-up, only one patient died; her HRV was lower than that of all the controls and was in the low range for DS patients. CONCLUSION: We describe for the first time an association between SE and HRV alterations in DS. Further studies on other SCN1A-related phenotypes and other epilepsies with frequent SE will help clarify this finding. Compared to the literature, our cohort showed better HRV and lower mortality. Although limited, this observation reinforces the role of HRV as a biomarker for mortality risk in DS.

Early Childhood Attention Battery: Italian adaptation and new expanded normative data.

BACKGROUND: The Early Childhood Attention Battery (ECAB) has been used to assess three different components of attention in preschool children, namely, selective, sustained and attentional control. AIM: The aim of the study was: I) to adapt the ECAB to the Italian language; II) to collect Italian reference data using the translated version and III) to expand the available reference data using 6-month age intervals. STUDY DESIGN: The adaptation of the ECAB to Italian language and the collection of Italian reference data was performed in four phases: translation and identification of the manual and subtests that needed adaptation; interobserver reliability and feasibility of the Italian version; application of the Italian ECAB; statistical analysis. SUBJECTS: The ECAB was performed on a low risk population between 3 and 5 years, 11 months. RESULTS: Statistical analysis was conducted subdividing the cohort in 6-month age groups. The final cohort included 300 low-risk typically developing children. The assessment was well accepted and enjoyed by most of the children except for some in the youngest group who refused to complete all of the tests. Our data showed a progressive improvement in attention across age in seven of the eight subtests of the ECAB. CONCLUSION: The ECAB is a feasible battery in Italian as in the English version, for the assessment of early attention in preschool children, allowing the assessment of the different components of attention and a specific maturation follow up with increasing age.

Early visual and neuro-development in preterm infants with and without retinopathy.

BACKGROUND: Retinopathy of prematurity (ROP) is often associated with visual impairment and multiple developmental disabilities. AIMS: As most of the previous studies include infants with brain lesions, that can determine visual impairment per se, a cohort of low neurological risk preterm infants without ROP and with various degree of severity of ROP was assessed in order to establish visual and neurodevelopmental outcome. STUDY DESIGN: Preterm infants born at <31 weeks gestation, without major brain lesions, underwent visual function assessment at 1 year corrected age and neurodevelopmental assessment at 2 years corrected age. SUBJECTS: One hundred and five infants were included in the study: 42 infants did not develop ROP, 7 reached stage 1 in zone 2 ROP, 37 reached prethreshold (untreated) type 2 ROP. The remaining 19 infants were classified as type 1 ROP. OUTCOME MEASURES: Visual function (including fixing, tracking, visual acuity, visual field, attention at distance and nystagmus) were assessed at 12 months corrected age and Griffiths Scales at 2 years corrected age. RESULTS: The severity of ROP was strongly correlated (p < 0.001) with both visual function at 1 year and neurodevelopment at 2 years. Similarly, the presence of nystagmus was also strongly correlated with visual and neurodevelopmental sequelae. CONCLUSIONS: Infants with no or milder retinopathy showed normal visual function at 1 year and neurodevelopment at 2 years. Infants who underwent treatment more frequently showed abnormal results on several aspects of visual function. Presence of nystagmus appeared to increase the risk for abnormal visual function and neurodevelopmental outcome.

Sleep disorders in spinal muscular atrophy.

OBJECTIVE: To estimate the frequency of sleep disorders in young persons with type 2 and type 3 spinal muscular atrophy (SMA), and to evaluate the relationship between sleep disorders and different variables such as motor impairment, age, use of ventilation, and use of night orthoses. METHODS: A total of 85 young persons (6-25 years of age) with type 2 and type 3 SMA were assessed using the Sleep Disturbance Scale for Children (SDSC), a scale assessing different sleep factors, and the Hammersmith Functional Motor Scale Expanded (HFMSE), a scale evaluating motor impairment. RESULTS: An abnormal total sleep score was found in 16.4% of children with SMA; an additional 16.7% had an abnormal score on at least one of the sleep factors assessed by the SDSC. No specific correlation was observed between sleep disturbances and functional level as expressed by the SDSC and total HFMSE scores, but the relationship with individual items on the scale was different. The SDSC total score was significantly associated with the ability to half roll on both sides and to roll from prone to supine on the HMFSE. CONCLUSION: Our results demonstrate that sleep disorders are common in children with SMA.

Histological effects of givinostat in boys with Duchenne muscular dystrophy.

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.

Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy.

The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.

Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials.

The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients.

Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes.

Recent studies have suggested that in non-ambulant patients affected by spinal muscular atrophy the Upper Limb Module can increase the range of activities assessed by the Hammersmith Functional Motor Scale Expanded. The aim of this study was to establish 12-month changes in the Upper Limb Module in a cohort of non-ambulant spinal muscular atrophy patients and their correlation with changes on the Hammersmith Functional Motor Scale Expanded. The Upper Limb Module scores ranged between 0 and 17 (mean 10.23, SD 4.81) at baseline and between 1 and 17 at 12 months (mean 10.27, SD 4.74). The Hammersmith Functional Motor Scale Expanded scores ranged between 0 and 34 (mean 12.43, SD 9.13) at baseline and between 0 and 34 at 12 months (mean 12.08, SD 9.21). The correlation betweeen the two scales was 0.65 at baseline and 0.72 on the 12 month changes. Our results confirm that the Upper Limb Module can capture functional changes in non-ambulant spinal muscular atrophy patients not otherwise captured by the other scale and that the combination of the two measures allows to capture changes in different subgroups of patients in whom baseline scores and functional changes may be influenced by several variables such as age.

Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy.

The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores ≥33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids.

Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test.

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.

Sleep disturbances in preschool age children with cerebral palsy: a questionnaire study.

OBJECTIVES: The study aimed to analyze (i) the prevalence of sleep disorders in pre-school children with cerebral palsy (CP) using the Sleep Disturbance Scale for Children (SDSC), (ii) the possible association with motor, cognitive and behavioral problems, and (iii) the possible differences with typically developing children matched for age and gender. METHODS: One-hundred children with CP (age range: 3-5 years, mean: 3.8 years) were assessed using the SDSC, the Gross Motor Function Classification System (GMFCS), the Wechsler Preschool and Primary Scale of Intelligence, and the Child Behaviour Check List (CBCL) to assess sleep, motor, cognitive, and behavioral problems, respectively. Further 100 healthy children matched for age and sex were assessed using the SDSC. RESULTS: An abnormal total sleep score was found in 13% of children with CP while 35% had an abnormal score on at least one SDSC factor. SDSC total score was significantly associated with pathological internalizing scores on CBCL and active epilepsy on multivariate analysis. CP group reported higher significant median scores on SDSC total, parasomnias, and difficulty in initiating and maintaining sleep factors. CONCLUSIONS: In pre-school children sleep disorders are more common in children with CP than in healthy control group and are often associated with epilepsy and behavioral problems.

Sleep disorders in children with cerebral palsy: neurodevelopmental and behavioral correlates.

OBJECTIVES: We aimed to estimate the frequency of sleep disorders in children with cerebral palsy (CP) using the Sleep Disturbance Scale for Children (SDSC) and to evaluate the relations between sleep disorders and motor, cognitive, and behavioral problems. METHODS: One hundred and sixty-five children with CP ages 6-16 years (mean age, 11years) were assessed using the SDSC, the Gross Motor Function Classification System (GMFCS), the Wechsler Intelligence Scale for Children and the Child Behavior Check List (CBCL) to assess sleep, motor, cognitive, and behavioral problems, respectively. RESULTS: An abnormal total sleep score was found in 19% of children with CP; more than 40% of children had an abnormal score on at least one SDSC factor. The SDSC total score was significantly associated (P<.01) with mental retardation, epilepsy, CBCL scores, and level 5 on the GMFCS. CONCLUSIONS: Our results confirm that sleep disorders are common in children with cerebral palsy. The relationship between motor and cognitive behavior and epilepsy should be further explored to better understand how these factors influence one another to identify effective treatments and to improve the well-being of the child.

Longitudinal assessment of perceptual-motor abilities in pre-school preterm children.

OBJECTIVE: To verify the value of early perceptual-motor assessment in preterms. METHODS: The M-ABC2 was performed below the age 3 years-4 months and 1 year later. RESULTS: At 4 years children showed a significant improvement in the scores and reduced rate of refusals. CONCLUSION: Early findings may be related to delayed maturation.

LMNA-associated myopathies: the Italian experience in a large cohort of patients.

OBJECTIVES: Our aim was to conduct a comparative study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. METHODS: We performed a retrospective cohort study of 78 myopathic patients with LMNA mutation and 30 familial cases with LMNA mutation without muscle involvement. We analyzed features characterizing the various forms of LMNA-related myopathy through correlation statistics. RESULTS: Of the 78 patients, 37 (47%) had limb-girdle muscular dystrophy 1B (LGMD1B), 18 (23%) congenital muscular dystrophy (MDCL), 17 (22%) autosomal dominant Emery-Dreifuss muscular dystrophy 2 (EDMD2), and 6 (8%) an atypical myopathy. The myopathic phenotypes shared a similar cardiac impairment. Cardioverter defibrillator or pacemaker was implanted in 41 (53%) myopathic patients compared to 7 (23%) familial cases without muscle involvement (p = 0.005). Heart transplantation was performed in 8 (10.3%) myopathic patients and in none of the familial cases. Ten (12.8%) myopathic patients died; there were no deaths among the familial cases (p = 0.032). Missense mutations were found in 14 patients (82%) with EDMD2 and 14 patients (78%) with MDCL compared to 17 patients (45%) with LGMD1B and 4 (67%) atypical patients. Frameshift mutations were detected in 17 (45%) LGMD1B compared to 3 (18%) EDMD2, 1 (6%) MDCL, and 2 (33%) with atypical myopathy (p = 0.021). Furthermore, frameshift mutations were found in 30 of 73 patients (41%) with heart involvement compared to 4 of 35 (11%) without heart involvement (p = 0.004). CONCLUSIONS: Our data provided new insights in LMNA-related myopathies, whose natural history appears to be dominated by cardiac involvement and related complications.

Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes.

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of -15.8 (SD 77.3) m at 12 months, of -58.9 (SD 125.7) m at 24 months and -104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

The 6 minute walk test and performance of upper limb in ambulant duchenne muscular dystrophy boys.

The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.