Objective Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods We analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

Long-term survival outcome is determined by the choice of the treatment. NRA and TV can prolong survival, with NRA showing a lower survival probability at ages 24 and 48 months.

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SummaryBackground & aimsDifferent 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.Methods15 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).ResultsSMA 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).ConclusionsThis 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.

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.