Spinal Muscular Atrophy Children Research Articles

SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES: P.86Cognitive assessment in spinal muscular atrophy type 1-2 using eye tracking system

Spinal muscular atrophy (SMA) is a devastating inherited disorder caused by ubiquitous deficiency in the SMN protein. SMA main feature is the progressive loss of motor activity caused by motor neurons degeneration leading to muscle atrophy. Recent evidence suggests that SMA is a systemic disease. In the brain SMN is expressed in many cell types in addition to motoneurons. Brain morphology changes have been described, and circadian dysregulation, abnormal fatty acid metabolism have been observed. Symptoms of signs of a systemic disease may likely become increasingly apparent in treated children treated, where neuromuscular symptoms are alleviated and life extended. Literature on cognitive aspects of SMA type 1-2 is poor and divergent. Indeed, physical impairments make usual IQ tests often unusable in many SMA children. Therefore, we developed an eye tracking system (Tobii®) for the assessment of cognitive functions in SMA patients belonging to the severe end of the spectrum. The set of tests contains the following subtests: Matrix subtest of Weschler non-verbal scale of ability for the study of fluid reasoning and perceptual reasoning. Recognition subtest of Weschler non-verbal scale of ability for the study of visuo-spatial memory. Peabody picture vocabulary test for the study of receptive vocabulary (French). The chimeric animal stroop test to study inhibition. Face recognition subtest of NEPSY-II to study face encoding, discrimination and recognition. Picture complement test to study the spatial reasoning. Matching pair test. Fourty children from 2 to 12 years old were enrolled: 10 SMA type 1, 10 SMA type 2, and 20 age and sex matched control patients. The methodology and first results will be presented. At the era of new treatments, in particular for SMA type 1, many questions are opened and could be partially answered by this approach: What is the natural history of cognition in SMA type 1 (and 2)? What is the impact of new treatment? How to organize the environment of SMA type 1 children in order to achieve optimal cognitive development (language, cognition, participation)? The developed protocol aims at validating eye tracking assessment tool for cognitive functions in SMA type 1 and 2. This study will help to adapt the overall management of patients and to evaluate the impact on cognition of future SMA treatments.

Intrathecal administration of Nusinersen in type 1 SMA: successful psychological program in a single Italian center.

Nusinersen is the first approved drug to treat spinal muscular atrophy (SMA). Its periodic intrathecal delivery may cause psychological burden in infants and in their parents. We report our experience during expanded access program (EAP) for type 1 SMA in a single Italian center. Because of the occurrence of stress emotional states, anxious reactions and fear before, during, and after lumbar puncture (LP), a specific psychological intervention was implemented based on regulation of emotions, anticipatory expectations, and post-event attributions. Activities included the use of fairy tales, distraction, music play through listening preferred cartoon themes in the youngest children, and contextual games and solution of fun riddle quizzes in the oldest ones. State anxiety greatly reduced in children and their parents. Treatment of psychological aspects should therefore become an integral part of health care in SMA infants and children during Nusinersen treatment.

Spinal bracing and lung function in type-2 spinal muscular atrophy.

Respiratory muscle weakness associated with scoliosis in type-2 spinal muscular atrophy (SMA) leads to respiratory impairment. Spinal brace, generally utilized to slow scoliosis progression and support sitting, could worsen lung function and hamper cough maneuvers. Six home-treated type-2 SMA children (aged 6-15 years, subtype 2.1-2.5) were assessed to evaluate time-dependent influence of "static-balanced brace" on pulmonary function. Lung function tests, including peak expiratory flow (PEF), peak cough flow (PCF), maximal static inspiratory pressure (MIP), maximal static expiratory pressure (MEP), forced vital capacity (FVC), were performed. PEF, MEP, FVC parameters were higher in tests after wearing braces three-hours, PCF slightly higher and MIP slightly lower compared to upon awakening values. "Static-balanced brace" did not impair lung function in our sample of six type-2 SMA children; in addition, it seemed to support cough maneuvers. Double assessment is determinant for decisions concerning use/non-use of brace differently from the usual one time evaluation procedure (base level compared to level wearing brace).

P.430 - Use of the Microsoft Kinect during motor function assessments of patients with Spinal muscular atrophy children: Kinect-MFM study

P.430 - Use of the Microsoft Kinect during motor function assessments of patients with Spinal muscular atrophy children: Kinect-MFM study

Use of the Microsoft Kinect during motor function assessments of patients with spinal muscular atrophy children: Kinect-MFM study

Use of the Microsoft Kinect during motor function assessments of patients with spinal muscular atrophy children: Kinect-MFM study

Spontaneous Breathing Pattern as Respiratory Functional Outcome in Children with Spinal Muscular Atrophy (SMA).

IntroductionSMA is characterised by progressive motor and respiratory muscle weakness. We aimed to verify if in SMA children 1)each form is characterized by specific ventilatory and thoraco-abdominal pattern(VTAp) during quiet breathing(QB); 2)VTAp is affected by salbutamol therapy, currently suggested as standard treatment, or by the natural history(NH) of SMA; 3)the severity of global motor impairment linearly correlates with VTAp.Materials and methodsVTAp was analysed on 32 SMA type I (SMA1,the most severe form), 51 type II (SMA2,the moderate), 8 type III (SMA3,the mildest) and 20 healthy (HC) using opto-electronic plethysmography. Spirometry, cough and motor function were measured in a subgroup of patients.ResultsIn SMA1, a normal ventilation is obtained in supine position by rapid and shallow breathing with paradoxical ribcage motion. In SMA2, ventilation is within a normal range in seated position due to an increased respiratory rate(p<0.05) with reduced tidal volume(p<0.05) secondary to a poor contribution of pulmonary ribcage(%ΔVRC,P, p<0.001). Salbutamol therapy had no effect on VTAp during QB(p>0.05) while tachypnea occurred in type I NH. A linear correlation(p<0.001) was found between motor function scales and VTAp.ConclusionA negative or reduced %ΔVRC,P, indicative of ribcage muscle weakness, is a distinctive feature of SMA1 and SMA2 since infancy. Its quantitative assessment represents a non-invasive, non-volitional index that can be obtained in all children, even uncollaborative, and provides useful information on the action of ribcage muscles that are known to be affected by the disease.Low values of motor function scales indicate impairment of motor but also of respiratory function.

Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters.

Self-locomotion and spatial language and spatial cognition: insights from typical and atypical development.

Various studies have shown that occurrence of locomotion in infancy is correlated with the development of spatial cognitive competencies. Recent evidence suggests that locomotor experience might also be important for the development of spatial language. Together these findings suggest that locomotor experience might play a crucial role in the development of linguistic-cognitive spatial skills. However, some studies indicate that, despite their total deprivation of locomotor experience, young children with spinal muscular atrophy (SMA) have the capacity to acquire and use rich spatial representations including good spatial language. Nonetheless, we have to be cautious about what the striking performances displayed by SMA children can reveal on the link between motor and spatial development, as the dynamics of brain development in atypically developing children are different from typically developing children.

A Prospective, Randomized Controlled Trial of Valproic Acid in Ambulant Adults with SMA: The VALIANT Trial (S25.002)

Objective: To report the results of a randomized, double-blind, placebo-controlled trial of valproic acid (VPA) in ambulatory adults with spinal muscular atrophy (SMA). Background Much evidence suggests that VPA, a histone deacetylase inhibitor, might benefit patients with SMA by modulating SMN2 splicing to increase production of full-length SMN transcript from SMN2 . Five open-label human trials of VPA in SMA showed a benefit in strength and function. Design/Methods: This was a prospective, randomized, double blind, 12 month study in SMA adults over 18 years old. After two baseline assessments, subjects were randomized to VPA or placebo and then crossed over to the other group at six months. Patients were evaluated at 3, 6, and 12 months. Primary outcome was the six-month strength change by maximum voluntary isometric contraction testing. Secondary outcomes included adverse events and changes in ulnar compound motor action potential amplitude and motor unit number estimation, strength by handheld dynamometry, 6 minute walk test, pulmonary function, functional rating scale (SMAFRS), and quality of life assessment. Results: Thirty-three subjects (20 M, 13 F; mean age 37.1) were enrolled; 16 patients were initially on VPA and 17 on placebo. Three patients did not complete the study; two due to adverse events not related to VPA and one withdrew. There were no significant adverse events. There was no significant change in the primary or secondary outcome after six months of treatment. Conclusions: VPA at doses used in this study did not improve strength or function in ambulatory SMA adults, and is compatible with earlier published negative CARNI-VAL studies in SMA children. The Project Cure-SMA group is currently analyzing data from open label studies in infants with Type 1 that should provide additional important information on VPA and its effect on biomarkers. Supported by: This study was entirely funded by FSMA through the Project Cure Investigators Network, and NIH CCTS funding at Ohio State. Disclosure: Dr. Elsheikh has nothing to disclose. Dr. Kolb has nothing to disclose. Dr. King has nothing to disclose. Dr. Chelnick has nothing to disclose. Dr. Scott has nothing to disclose. Dr. LaSalle has nothing to disclose. Dr. Krosschell has nothing to disclose. Dr. Reyna has nothing to disclose. Dr. Swoboda has received research support from BioMarin Pharmaceuticals and Orphamed, Dr. Kissel has nothing to disclose.

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

BackgroundMultiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.MethodsThis study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.ResultsTwenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.ConclusionsThis study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA.Trial RegsitrationClinicaltrials.gov NCT00227266

Reliability of the modified hammersmith functional motor scale in young children with spinal muscular atrophy

The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.

Spinal muscular atrophy: a time for screening

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through carrier detection and prenatal diagnosis becomes extremely important. The correlation between the SMA phenotype and the SMN2 copy number and the demonstration that sufficient SMN protein from SMN2 in transgenic mice can ameliorate the disease has made the SMN2 gene an obvious target that is being modulated in current therapeutic trials. Most recent work, utilizing gene therapy, has also shown a rescue of the phenotype in the mouse model. Since SMA children are often asymptomatic at birth, newborn screening is a means which will allow the implementation of the most early intervention to take place, before the irreversible loss of motor neurons. Since there is no effective cure for SMA presently, prevention through the identification of carriers becomes an important alternative and has recently been initiated. Treatment and prevention of SMA are complementary responses to the scourge presented by SMA. This review first describes the molecular genetics of SMA and then focuses on newborn screening, as a means of ensuring the earliest intervention, and the prevention through population carrier screening.

Early locomotion and the development of spatial language: Evidence from young children with motor impairments

Recent studies show that young children with type-2 spinal muscular atrophy (SMA) can succeed in spatial search tasks. Such results suggest that locomotor impairment may not be a risk factor responsible for a dramatic slowing down or deviation in the development of spatial cognition. The present experiment pursues this question in relation to spatial language to determine whether self-produced locomotion is a necessary prerequisite for the normal acquisition of spatial terms. It compares how two groups of young French children (mean age 33 months) comprehend and produce spatial markers: one group of 12 type-2 SMA children and a control group of 12 healthy children. The results show no significant difference between the two groups with one exception: SMA children displayed a better performance when producing markers for the relations in front of and behind. The performance of SMA children suggests that, despite their total deprivation of experience in locomotion, they have the capacity to acquire and to use rich spatial representations that are embodied in the semantics of natural languages.

Childhood spinal muscular atrophy induces alterations in contractile and regulatory protein isoform expressions

Although modifications of the survival motor neurone gene are responsible for most spinal muscular atrophy (SMA) cases, the molecular pathophysiology and the muscular target proteins involved are still unknown. The aim of this study was to compare the expression of contractile and regulatory protein isoforms in quadriceps muscles from SMA children with age-matched control quadriceps. The isoform patterns of myosin heavy chains (MHC), troponin subunits (T, C and I) and tropomyosin were determined by immunoblotting, reverse transcription-polymerase chain reaction and mass spectrometry analyses. Depending on the disease severity, their expression levels were followed in specific variants of SMA populations (types I, II and III), with comparison with age-matched control muscles. The isoform transitions in SMA muscles were different from the fast-to-faster transitions occurring in normal muscles from children aged 1 month to 5 years old. Moreover, the expression of the neonatal MHC isoform was not repressed in SMA muscles. The presence of the neonatal MHC isoform in SMA muscles indicates an alteration of the phenotype in these diseased muscles. It is strongly suggested that MHC and troponin T proteins may be good markers for the SMA pathology.

Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007,

Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France

Locomotion autonome et cognition spatiale : le paradoxe de l'amyotrophie spinale infantile

Various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. However, recent studies indicate that young children with spinal muscular atrophy (SMA), a hereditary neuromuscular disease which results in severe motor impairments, excel in some spatial cognitive skills. Indeed, striking cognitive performances are exhibited by young SMA children in some areas such as the ability to search successfully for hidden objects and the acquisition of the spatial vocabulary. The performances of SMA children suggest that, despite their total deprivation of locomotor experience, they have the capacity to acquire and use rich spatial representations. As a result, locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills.

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra- and interrater reliability and the test–retest stability of a modified version of the scale. Both intra- and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20°. These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

Caractéristiques psychologiques des enfants et des adolescents atteints d'amyotrophie spinale infantile

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease characterized by severe progressive muscular weakness related to a degeneration of the anterior horn cells of the spinal cord. This rare genetic disorder (incidence 1/6000) is caused by a microdeletion on chromosome 5q13. Recent studies indicate that young children with SMA excel in specific cognitive skills. These results suggest that the motor impairment of SMA children begins from early on to shape specific aspects of intelligence and language.

Spinal Muscular Atrophy: Survival Pattern and Functional Status

Spinal Muscular Atrophy: Survival Pattern and Functional Status

Bone Mineral Density in a Paediatric Spinal Muscular Atrophy Population

Reduced bone mineral density is a feature of patients with reduced mobility. The aim of this study was to assess bone mineral density in children with spinal muscular atrophy (SMA) and to evaluate bone mineral density in relation to age and motor disability. We analysed bone mineral density measurements on twelve patients (4 with SMA type II, mean age 8.2 years [range 6.2 - 11.8]; 8 with SMA type III, mean age 11.8 years [range 5.5 - 20]). Dual-energy X-ray absorptiometry (DXA) was used to determine total body bone mineral density. The results were matched with published normative data for age and sex for a white Caucasian population. The total body bone mineral density values were in the normal range in 10 out of the 12 SMA patients studied, all below the age of 17 (mean age 8.8 years [range 5.5 - 16.33]). Four of them had SMA II and six had had SMA III and were still ambulant. Total body bone mineral density was, however, below 2 SD in the remaining 2 patients aged 19.7 and 20 years, respectively. Both had SMA III but had lost independent ambulation for a period of 3.5 years. Our results suggest that bone mineral density was surprisingly normal in most of the young SMA children studied. This is in contrast to what is reported in other conditions characterised by reduced mobility such as Duchenne muscular dystrophy. However, there was a tendency to decreasing bone mineral density with increasing age, not always related to the ability to walk, with the two eldest patients having the lowest values in spite of a relatively good mobility. These findings suggest that factors other than mobility are likely to have an effect on SMA bone mineral density.