Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials.

Objective Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. Methods A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. Results Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17). Interpretation These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated.

Background: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma ® ) gene replacement therapy, are emerging. Objective: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants. Methods: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events. Results: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively).

We have investigated the 57Fe Mössbauer quadrupole splittings in the following compounds by using density functional theory, and in some cases via experiment:  Fe(CO)3(cyclo-butadiene), Fe(CO)5, Fe(CO)3(1,4−butadiene), CpFe(CO)2Me, Fe(CO)3(propenal), CpFe(CO)2Cl, (CO)(pyridine)(DMGBPh2)2Fe(II) (DMG = dimethylglyoximato), (CO)(pyridine)(DMGBBN)2Fe(II) (BBN = 9-borabicyclo[3.3.1]nonane), (CO)(1-methylimidazole)(5,10,15,20-tetraphenylporphinato)Fe(II), (CO)(pyridine)(5,10,15,20-tetraphenyl-porphinato)Fe(II), (nitrosobenzene)(pyridine)(5,10,15,20-tetraphenylporphinato)Fe(II), (pyridine)2(5,10,15,20-tetraphenylporphinato)Fe(II), (1-methylimidazole)2(5,10,15,20-tetramesitylporphinato)Fe(II), and (trimethylphosphine)2(2,3,7,8,12,13,17,18-octaethylporphinato)Fe(II). The electric field gradients at iron were evaluated by using a locally dense basis approach:  a Wachters' all electron representation for iron, a 6-311++G2d basis for all atoms directly bonded to iron, and either a 6-31G* basis for all other atoms or, in the case of the metalloporphyrins, a 6-31G*/3-21G* or 4-31G* basis, with the smaller basis being used on the peripheral atoms. Using a value of 0.16 × 10-28 m2 for the quadrupole moment of 57Fem, we find good agreement between theoretical and experimental quadrupole splittings:  a slope of 1.04, an R 2 value of 0.975, and a root-mean-square error of 0.18 mm s-1, for the 14 compounds examined. We have also investigated the effects of the CO ligand tilt and bend on the 57Fe quadrupole splittings in several heme models. The theoretical results provide no support for the very large (40°) Fe−C−O bond angles suggested by several diffraction studies on Physeter catodon carbonmonoxymyoglobin (P21 crystals). In contrast, the experimental results for (CO)(1-MeIm)(5,10,15,20-tetraphenylporphinato)Fe(II), which contains a linear and untilted Fe−CO, are in very close accord with the experimental values for CO-myoglobin:  0.35 mm s-1 for the model system versus 0.363−0.373 mm s-1 for MbCO, with V zz oriented perpendicular to the porphyrin plane, as found experimentally. Calculations on metalloporphyrins at the more distorted X-ray geometries yield quadrupole splittings around 2 mm s-1, inconsistent with experiment.

Background Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent‐ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS‐101 gene replacement therapy. Methods Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one‐time intravenous proposed therapeutic dose of AVXS‐101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2‐years post‐treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function. Results All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. Conclusions AVXS‐101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow‐up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy. Trial registration http://ClinicalTrials.gov number, NCT02122952.