in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein d o m a i n , w i t h e ff e c t s on p o p u l a t i o n ge n e t i c c h a r a c t e r i s t i c s a n d ne w personalized therapies.

S87 delay, intellectual disability, microcephaly, delayed brain myelination, and recurrent seizures, ultimately resulting in the death of most patients before the age of twenty. However, the function of UBA5 in the nervous system and how mutation of UBA5 results in disease was not known. To investigate the pathophysiology associated with UBA5 mutation and to identify pathways that could reduce disease progression we are using the zebrafish. We show that uba5 loss of function in zebrafish leads to significant decrease in locomotor activity, recapitulating the motor dysfunction observed in UBA5 patients. Notably, the motor impairment is not preceded by damage to the overall neuronal network and muscle morphology. However, electron microscopy reveals signs of degradation and aggregates in the nerves innervating the skeletal muscle of uba5 mutants. This finding suggests that there may be an early sub-clinical phenotype in the peripheral nervous system that could contribute to the pathology observed in UBA5 patients. We also identify a dramatic reduction in growth. We describe the identification of the pathways disrupted by the loss of Uba5 , explaining the epileptic symptoms, growth defects, and neurodegeneration observed in patients.

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In healthy children, whole body lean mass (WB-LM) by dual-energy xray absorptiometry (DXA) is a surrogate for muscle mass and is associated with WB bone mineral density (WB-BMD), and muscle strength. The purpose of this study was to explore whether these relationships are preserved in Duchenne muscular dystrophy (DMD). We also explored the relationship between WB-LM and bone metabolism, in view of the frequent bone fragility in pediatric DMD. Baseline data in ambulatory boys 4 to 7 years of age (up to 8 th birthday) with genetically-confirmed DMD not on corticosteroids who were participating in a global phase III trial of the NF-kB inhibitor edasalonexent (NCT03703882) were analyzed. Treatmentnaïve boys underwent the North Star Ambulatory Assessment (NSAA), and DXA for WB-LM (expressed as LM Index = LM/height 2 , kg/m 2), and WB-BMD, g/cm 2. 72 boys, mean age of 5.9 ±1.1 years, were included in this analysis. The mean NSAA total score was 20.4 ±4.7. Compared to boys with a NSAA score < 20, those with NSAA ≥ 20 were taller (113.3 ±8.7 versus 108.2 ±8.4 cm; p = 0.015), and heavier (21.6 ±3.8 versus 19.4 ±3.8 kg; p = 0.019). In multivariable regression models, LM index was a significant factor associated with WB-BMD (β 0.018, 95% Confidence Interval (CI) 0.009, 0.028; p < 0.001), and NSAA total score (β 0.1.352, 95% CI 0.306, 2.399; p = 0.012). LM index was also independently associated with tartrateresistant acid phosphatase 5b (TRAP-5b, a bone resorption marker, β-0.698, 95% CI-1.313,-0.082; p = 0.027, controlling for age and height). In this study, the relationships between LM index and WB-BMD, and between LM index and muscle function assessed by NSAA were preserved. These results show that LM index correlates with muscle function and WB-BMD in young, ambulatory boys with DMD. The inverse relationship between LM index and TRAP5b suggests skeletal resorption is higher in young DMD boys with DMD reduced muscle mass.