Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Clinical and Functional Characteristics of a New Phenotype of SMA Type I among a National Sample of Spanish Children: A Cross-Sectional Study.

Spinal Muscular Atrophy (SMA) type I has classically presented extremely severe clinical features. New pharmacological treatments have led to a new phenotype of SMA. The aim of this study was to describe the current health and functional status of children with SMA. A cross-sectional study was conducted based on the STROBE guidelines. Patient questionnaires and standardized tools were used. A descriptive analysis was conducted establishing the proportions of subjects for each of the characteristics of interest. In total, 51 genetically confirmed SMA type I subjects were included. Fifty-seven percent received oral feeding, 33% received tube feeding and 10% combined both. Moreover, 21.6% had tracheostomies, and 9.8% needed more than 16 h/d ventilatory support. Regarding orthopedic status, 66.7% had scoliosis, and 68.6% had hip subluxation or dislocation. Up to 67% were able to sit independently, 23.5% walked with support and one child walked independently. Current SMA type I is a different entity from the classic phenotype but also from types II and III. In addition, no differences were found between SMA type I subgroups. These findings may enable the professionals involved in the care of these patients to improve their interventions in terms of prevention and rehabilitation measures for these children.

Natural history in spinal muscular atrophy Type I in Taiwanese population: A longitudinal study.

INTRODUCTION: Spinal muscular atrophy (SMA) is caused by a defect in the survival motor neuron 1 (SMN1) gene. The Cooperative Study of the natural history of SMA Type I in Taiwan is a retrospective, longitudinal, observational study that helps in further understanding SMA disease progression in patients who have not received disease-modifying therapeutic interventions. METHODS: Case report forms were used to collect demographics; genetic confirmation; SMN2 copy number; treatment patterns; and clinical outcomes including ventilator use, endotracheal tube intubation, tracheostomy, gastrostomy, complications, and survival. RESULTS: A total of 111 patients with SMA Type I were identified over the study period (1979-2015). Mean (median) age of onset and age at confirmed diagnosis were 1.3 (0.8) and 4.9 (4.4) months, respectively. SMN1 deletion/mutation was documented in 70 patients and SMN2 copy number in 32 (2 copies, n = 20; 3 copies, n = 12). At 240 months, survival probability for patients born during 1995-2015 versus 1979-1994 was significantly longer (p = 0.0057). Patients with 3 SMN2 copies showed substantially longer 240-month survival versus patients with 2 SMN2 copies. Over the 36-year period, mean (median) age at death was 31.9 (8.8) months. As of December 2015, 95 patients had died, 13 were alive, and 3 were lost to follow-up. The use of supportive measures (tracheostomy and gastrostomy) was associated with improved survival. CONCLUSIONS: These data describe the short survival of patients with SMA Type I in Taiwan in the pretreatment era, emphasizing the positive impact of supportive measures on survival.

Predictive fat mass equations for spinal muscular atrophy type I children: Development and internal validation.

BACKGROUND: Body composition assessment is paramount for spinal muscular atrophy type I (SMA I) patients, as weight and BMI have proven to be misleading for these patients. Despite its importance, no disease-specific field method is currently available, and the assessment of body composition of SMA I patients requires reference methods available only in specialized settings. OBJECTIVE: To develop predictive fat mass equations for SMA I children based on simple measurements, and compare existing equations to the new disease-specific equations. DESIGN: Demographic, clinical and anthropometric data were examined as potential predictors of the best candidate response variable and non-linear relations were taken into account by transforming continuous predictors with restricted cubic splines. Alternative models were fitted including all the dimensions revealed by cluster analysis of the predictors. The best models were then internally validated, quantifying optimism of the obtained performance measures. The contribution of nusinersen treatment to the unexplained variability of the final models was also tested. RESULTS: A total of 153 SMA I patients were included in the study, as part of a longitudinal observational study in SMA children conducted at the International Center for the Assessment of Nutritional Status (ICANS), University of Milan. The sample equally represented both sexes (56% females) and a wide age range (from 3 months to 12 years, median 1.2 years). Four alternative models performed equally in predicting fat mass fraction (fat mass/body weight). The most convenient was selected and further presented. The selected model uses as predictors sex, age, calf circumference and the sum of triceps, suprailiac and calf skinfold thicknesses. The model showed high predictive ability (optimism corrected coefficient of determination, R2 = 0.72) and internal validation indicated little optimism both in performance measures and model calibration. The addition of nusinersen as a predictor variable did not improve the prediction. The disease-specific equation was more accurate than the available fat mass equations. CONCLUSIONS: The developed prediction model allows the assessment of body composition in SMA I children with simple and widely available measures and with reasonable accuracy.

Spinal muscular atrophy (SMA) type I (Werdnig-Hoffmann disease).

Spinal muscular atrophy type I, also called Werdnig-Hoffmann disease, is the most serious form. The disease appears before the age of 6 months and is characterized by major global hypotonia and abolition of tendon reflexes, with children never being able to sit unaided. Cognitive development is normal and the expressive gaze of these children contrasts with the paralytic attitude. Respiratory involvement predominates in the intercostal muscles, and sometimes brainstem involvement are all serious aspects of the disease. Type I spinal muscular atrophy has been subdivided into 3 groups: - type IA, the clinical signs of which set in between birth and 15 days of life with sudden severe motor impairment, sucking-swallowing disorders attesting to bulbar involvement, respiratory distress. - type IB with onset of symptoms before the age of 3 months, which implies no head control - type IC starting between 3 and 6 months with the possibility of checking head control, often referred to as "I bis" by French practitioners. The development and use of innovative therapies in recent years does actually change the natural course of this disease. But we do not know for sure what the long-term evolution of infants who received these new therapies will be. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Autopsy of a child with Spinal muscular atrophy Type I (Werdnig-Hoffmann disease).

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.

Predictive energy equations for spinal muscular atrophy type I children.

BACKGROUND: Knowledge on resting energy expenditure (REE) in spinal muscular atrophy type I (SMAI) is still limited. The lack of a population-specific REE equation has led to poor nutritional support and impairment of nutritional status. OBJECTIVE: To identify the best predictors of measured REE (mREE) among simple bedside parameters, to include these predictors in population-specific equations, and to compare such models with the common predictive equations. METHODS: Demographic, clinical, anthropometric, and treatment variables were examined as potential predictors of mREE by indirect calorimetry (IC) in 122 SMAI children consecutively enrolled in an ongoing longitudinal observational study. Parameters predicting REE were identified, and prespecified linear regression models adjusted for nusinersen treatment (discrete: 0 = no; 1 = yes) were used to develop predictive equations, separately in spontaneously breathing and mechanically ventilated patients. RESULTS: In naïve patients, the median (25th, 75th percentile) mREE was 480 (412, 575) compared with 394 (281, 554) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.009).In nusinersen-treated patients, the median (25th, 75th percentile) mREE was 609 (592, 702) compared with 639 (479, 723) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.949).Both in spontaneously breathing and mechanically ventilated patients, the best prediction of REE was obtained from 3 models, all using as predictors: 1 body size related measurement and nusinersen treatment status. Nusinersen treatment was correlated with higher REE both in spontaneously breathing and mechanically ventilated patients. The population-specific equations showed a lower interindividual variability of the bias than the other equation tested, however, they showed a high root mean squared error. CONCLUSIONS: We demonstrated that ventilatory status, nusinersen treatment, demographic, and anthropometric characteristics determine energy requirements in SMAI. Our SMAI-specific equations include variables available in clinical practice and were generally more accurate than previously published equations. At the individual level, however, IC is strongly recommended for assessing energy requirements. Further research is needed to externally validate these predictive equations.

Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination-Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. RESULTS: Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. CONCLUSION: Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.

Spinal Muscular Atrophy, types I and II: What are the differences in body composition and resting energy expenditure?

BACKGROUND & AIMS: Different neuromuscular functional domains in types I and II Spinal Muscular Atrophy (SMAI and SMAII) could lead to differences in body composition (BC) and resting energy expenditure (REE). Their identification could provide the key to defining appropriate strategies in clinical dietary management, but data comparing SMAI and SMAII in terms of BC and REE are not yet available. We measured total and regional fat (FM), lean (LBM), mineral (BMC) masses, body water (total, intra- and extra-cellular, TBW, ICW, ECW) and REE in a sample of SMAI and II children, matched for age and sex, and also adjusting for body size to compare these features of the two SMA phenotypes. METHODS: 15 SMAI and 15 SMAII children, (M/F = 9/6 vs 9/6, age 3.6 ± 1.9 vs 3.5 ± 1.8 years, p = 0.99), confirmed genetically, were measured as follows: Anthropometric measurements [Body Weight (BW), Supine Length (SL), Arm Length (AL), Femur Length (FL), Tibia Length (TL)], Dual x-ray Energy Absorptiometry (DEXA) [total and segmental FM, LBM, FFM, and BMC], Bioelectrical impedance (BIA) [TBW, ICW, ECW] and Indirect Calorimetry (REE, respiratory quotients) were collected by the same trained dietician. BW, SL and Body Mass Index (BMI) Z-scores were calculated according to CDC Growth Charts (2000). RESULTS: SMA children had high percentages of FM and a lower percentage of TBW and ECW compared to the respective reference values for sex and age, whereas the BMC percentages did not differ, even splitting the two phenotypes. SMA I children had a lower BW and BMI-Z score compared to children with SMA II, but similar total and segmental FM. On the contrary, total FFM and LBM were significantly lower in SMAI (7290.0 ± 1729.1 g vs 8410.1 ± 1508.4 g; 6971.8 ± 1637.1 g vs 8041.7 ± 1427.7 g, p = 0.039, p = 0.037, respectively), particularly at the trunk level. Arm BMC also resulted significantly lower in SMAI. The measured REE values were similar (684 ± 143 kcal/day vs 703 ± 122 Kcal/day p = 0.707) whereas REE per FFM unit was higher in SMA I children than in SMA II (95 ± 12 kcal/FFMkg vs 84 ± 11 kcal/FFMkg p = 0.017). CONCLUSIONS: This study has shown that BW and BMI Z-score measurements alone can be misleading in assessing nutritional status, particularly in SMAI. The differences between SMAI and II in total and regional BC are related only to FFM, LBM and BMC, and seem to be more linked to the magnitude of neurofunctional impairment rather than to the nutritional status derangement. SMA I and SMA II children can have different energy requirements in relation to their specific BC and hypermetabolism of FFM. Based on these results, our recommendation is to use direct BC and REE measurements in the nutritional care process until SMA-specific predictive equations become available.

Neuroblastoma in a Patient With Spinal Muscular Atrophy Type I: Is It Just a Coincidence?

Spinal muscular atrophy is an autosomal recessive disorder characterized by progressive degeneration of anterior horn cells of the spinal cord resulting in hypotonia, skeletal muscle atrophy, and weakness. Herein, we report a 4-month-old male infant who presented to our hospital with an abdominal mass that was diagnosed as neuroblastoma and spinal muscular atrophy type I. We would like to discuss the course and differential diagnosis with an algorithm leading to the diagnosis in this peculiar patient. To our knowledge, coexistence of spinal muscular atrophy type I and neuroblastoma is defined for the first time in the literature.

Autopsy of a child with Spinal muscular atrophy Type I (Werdnig-Hoffmann disease)

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.

Frequency of SMN1 deletion carriers in a Mestizo population of central and northeastern Mexico: A pilot study.

Individuals who suffer from spinal muscular atrophy (SMA) exhibit progressive muscle weakness that frequently results in mortality in the most severe forms of the disease. In 98% of cases, there is a homozygous deletion of the survival of motor neuron 1 (SMN1) gene, and both parents carry the same heterozygous genetic abnormality in the majority of cases. Various population studies have been conducted to estimate the frequency of carriers and thereby identify the communities or countries in which children are at a high risk of being affected by SMA. However, the prevalence of SMA in Mexican populations has not yet been established. In the present pilot study, the frequency of the heterozygous deletion of the SMN1 gene was determined in two groups from northeastern (n=287) and central (n=133) Mexican Mestizo populations and compared with other ethnic populations. Amplification refractory mutation system polymerase chain reaction analysis yielded a disease carrier frequency of 11/420 (2.62%) healthy individuals, comprising 9/287 (3.14%) northeastern and 2/133 (1.5%) central Mexican individuals. In summary, no significant differences were identified between the northeastern and central populations of Mexico and other ethnic populations, with the exception of the general worldwide Hispanic population, which exhibited the lowest carrier frequency of 8/1,030. The results of the present study may be used to improve the evaluation procedure, and appear to justify further studies involving larger sample populations.

Nutritional practices at a glance: spinal muscular atrophy type I nutrition survey findings.

Proactive nutritional management for children with spinal muscular atrophy type I can provide insight into improved spinal muscular atrophy care. This observational study consisted of a nutritional and medical history survey of children with spinal muscular atrophy type I collected in 2009-2011. Forty-four caregiver survey responses were evaluated using descriptive statistics. Average age of spinal muscular atrophy type I subjects was 5 years (5 mo-16 y). The subject cohort was composed of 22 males, 21 females, and 1 unreported. Nutrition support via feeding tube was utilized by 43 of 44 subjects. A majority of respondents reported using elemental or semi-elemental formula for subjects' essential caloric intake (34 of 44). Formula intolerance issues were reported by many caregivers (27 of 44). Half of caregivers implemented dietary changes on their own or with guidance from other families; 15 caregivers consulted a registered dietitian. Survey responses and comments indicate need for evidence-based nutritional guidelines for spinal muscular atrophy.

Vitamin D intake is inadequate in spinal muscular atrophy type I cohort: correlations with bone health.

Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.