Evaluation of body composition as a potential biomarker in spinal muscular atrophy.

INTRODUCTION: We aimed to investigate the correlation between body composition (BC) and spinal muscular atrophy (SMA)-specific motor function assessments. METHODS: Patients with SMA types I or II, aged 1 to 10 years, were recruited in this cross-sectional study. The protocol included anthropometric measurements, and dual-energy X-ray absoprtiometry to assess fat mass (FM), lean mass (LM), fat-free mass (FFM), FM and FFM indexes (FMI, FFMI), and motor function assessments (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale for SMAI, and Hammersmith Functional Motor Scale-Expanded for SMAII). RESULTS: Eighty-eight children were included. All had a higher FM percentage than reference values. Motor function was moderately correlated with body mass index (BMI), FFMI, and LMI in SMAI, and weakly correlated with FFMI, LMI, and LM:FM ratio in SMAII. DISCUSSION: BC shows promise as a potential biomarker for SMA, but further studies are needed.

3D Facial morphology in children affected by spinal muscular atrophy type 2 (SMAII).

OBJECTIVES: The main objective of this study was to assess the three-dimensional facial characteristics of children affected by spinal muscular atrophy (SMA), a severe muscular disorder characterized by hypotonia, areflexia, weakness, and respiratory impairment. MATERIALS/METHODS: Stereophotogrammetric facial scans from 22 SMA type II patients aged 2-7 years were obtained. Data were analysed using both inter-landmark distances and principal component analysis and compared with data collected from matched control subjects. RESULTS: Patients had wider transverse facial diameters, but smaller biocular width. Middle and lower anterior face heights were increased, whereas the mandibular ramus was shorter, with a reduced posterior-to-anterior face height ratio. Facial width-to-length ratio was reduced. In the sagittal plane, mandibular body length, and facial divergence were increased, whereas the gonial angles were decreased. In the horizontal plane, lower facial convexity was greater in patients, whereas mandibular convexity was smaller. Patients had smaller and down-slanted eye fissures, with a larger and more vertically developed nose. LIMITATIONS: This study assessed a relatively small number of patients, due to the rare frequency of SMA type II. CONCLUSIONS/IMPLICATIONS: SMA type II children possess peculiar facial alterations that may be due to the altered muscular activity. As feeding problems may derive also by malocclusion and masticatory muscular alterations, a detailed assessment of the craniofacial individual alterations should be considered in the standards of care of these patients.

Intellectual abilities, language comprehension, speech, and motor function in children with spinal muscular atrophy type 1.

BACKGROUND: Spinal muscular atrophy (SMA) is a chronic, neuromuscular disease characterized by degeneration of spinal cord motor neurons, resulting in progressive muscular atrophy and weakness. SMA1 is the most severe form characterized by significant bulbar, respiratory, and motor dysfunction. SMA1 prevents children from speaking a clearly understandable and fluent language, with their communication being mainly characterized by eye movements, guttural sounds, and anarthria (type 1a); severe dysarthria (type 1b); and nasal voice and dyslalia (type 1c). The aim of this study was to analyze for the first time cognitive functions, language comprehension, and speech in natural history SMA1 children according to age and subtypes, to develop cognitive and language benchmarks that provide outcomes for the clinical medication trials that are changing SMA1 course/trajectory. METHODS: This is a retrospective study including 22 children with SMA1 (10 affected by subtype 1a-1b: AB and 12 by 1c: C) aged 3-11 years in clinical stable condition with a coded way to communicate "yes" and "no". Data from the following assessments have been retrieved from patient charts: one-dimensional Raven test (RCPM), to evaluate cognitive development (IQ); ALS Severity Score (ALSSS) to evaluate speech disturbances; Brown Bellugy modified for Italian standards (TCGB) to evaluate language comprehension; and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) to assess motor functioning. RESULTS: SMA 1AB and 1C children were similar in age, with the former characterized by lower CHOP-INTEND scores compared to the latter. All 22 children had collaborated to RCPM and their median IQ was 120 with no difference (p = 0.945) between AB and C. Global median score of the speech domain of the ALSSS was 5; however, it was 2 in AB children, being significantly lower than C (6.5, p < 0.001). TCGB test had been completed by 13 children, with morphosyntactic comprehension being in the normal range (50). Although ALSSS did not correlate with both IQ and TCGB, it had a strong (p < 0.001) correlation with CHOP-INTEND described by an exponential rise to maximum. CONCLUSIONS: Although speech and motor function were severely compromised, children with SMA1 showed general intelligence and language comprehension in the normal range. Speech impairment was strictly related to global motor impairment.

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.

Growth patterns in children with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. RESULTS: Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4-1.6) and 4.1 (2.1-6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. CONCLUSIONS: These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.

Feeding difficulties in children and adolescents with spinal muscular atrophy type 2.

Disease course of feeding difficulties in spinal muscular atrophy type 2 is not well documented. Disease-modifying therapies rapidly change the trajectory of motor function and survival in spinal muscular atrophy, but effects on co-morbidities like bulbar function are unknown. We analysed data concerning feeding problems and their standard of care treatment in 146 patients with spinal muscular atrophy type 2. Data were collected from two separate cohorts: one single-centre retrospective chart review study from the United Kingdom (London), and one prospective questionnaire-based multicentre study from Italy. Cumulatively feeding difficulties were present in 88 patients (60%) in these 2 cohorts. Median age at onset of problems was 6.5years (range 0-16.5 years). Eighty-two patients (60%) showed periods of underweight according to age adjusted body mass index, and thirty-six patients (25%) showed malnourishment with a significant drop on their weight curves. Enteral feeding was indicated in 23 out of 72 patients in the UK cohort (32%) because of weight loss, oropharyngeal dysphagia or aspiration. Gastrostomy and its placement was generally well tolerated, uncomplicated in 96%, never reversed and performed without Nissen fundoplication in 66% of patients. After gastrostomy chest infections improved in 80% and nutritional status (e.g., Body Mass Index) in 84% of patients. These results show that feeding difficulties are a common problem in spinal muscular atrophy type 2. Treatment strategies should be tailor-made on the symptoms and needs of the individual patient.

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.