Exploring the Physiologic, Pharmacodynamic, and Clinical Responses of Skeletal Muscle in Patients With Spinal Muscular Atrophy Treated With SMN-Directed Therapies

MR functional imaging is considered feasible if ≥ 80% of MRI protocol eligible patients can complete 100% of imaging assessments at baseline and 6 months.

MR functional imaging is considered reliable if the test-retest reliability is ≥ 0.80 for key imaging biomarkers.

Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure phosphocreatine within the muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.

Real-time 31P MR spectroscopy and CrCEST MRI will be used to measure creatine concentrations within the muscles at rest, during an exercise protocol, and during post-exercise recovery to baseline. Both measure the recovery time in seconds.

Measurement of thickness of muscle compared to fat on MRI, measured in percentage.

Electrophysiological testing: Compound motor action potential (CMAP, measured in millivolts), motor unit number estimate (MUNE, average 200-400 for most limb muscles), and repetitive stimulation at 3 Hz - right ulnar to abductor digiti minimus and right fibular/peroneal nerve to tibialis anterior muscle.

A decrease of more than 40% in the amplitude of CMAP is considered abnormal.

The Hammersmith Functional Motor Scale Expanded (HFMSE) has a score range from 0-66 with lower scores indicating poorer overall motor function.

The Revised Upper Limb Module (RULM) has a score range 0-37 with lower scores indicating poorer upper limb motor function.

The Block and Box Test (BBT) is a measure of gross manual dexterity and is scored by counting the number of blocks carried from one compartment to another. Higher scores are indicative of better manual dexterity.

The 6-Minute Walk (6MW) Test measures how far someone can walk in six minutes, a higher score indicates better exercise tolerance score. A low score correlates with lower function.

The 10 Meter Walk/Run (10MW) Test is measured in seconds and assesses walking speed over a short distance. Longer times indicate lower motor function

The 4-Stair Climb (4SC) Test is measured in seconds and assesses lower extremity power and motor function. Longer times indicate lower motor function

The Supine-to-Stand (STS) Test is measured in seconds and assesses the ability to move from laying on your back to standing up straight. Longer times indicate lower motor function.

The Timed Up-and-Go (TUG) Test is measured in seconds and assesses the ability to stand up from sitting in a chair, walk 10 feet, turn around, walk back, and sit down. Longer times indicate lower motor function

Myometry measures force in pounds or kilograms and measures the strength of a muscle group. The more force measured indicates more muscle strength.

Muscle thickness is measured in centimeters and echogenicity is measured in gray-scale value. Muscle thickness and echogenicity are related to muscle strength, physical function, muscle mass, and quality of muscle.

The NF-L and pNF-H levels are measured in nanograms per milliliter from blood samples and can be an indicator of nerve cell damage. Higher values normally mean more nerve damage is occurring.

SMN protein levels are measured in nanograms per milliliter from blood samples. Higher values indicate more SMN protein production which is normally deficit in people with SMA.

This parameters has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. A normal blood pyruvic acid level is between 0.3 and 1.5 milligrams per deciliter (mg/dL). Elevated pyruvic acid in glycolysis usually indicates a disruption in the normal metabolic pathway.

This parameter has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. Normally, blood lactate levels are between 1-2 mmol/L when not exercising. Elevated lactic acid during glycolysis indicates that the body is primarily relying on anaerobic glycolysis, meaning it is breaking down glucose for energy without sufficient oxygen, leading to a buildup of lactate as a byproduct.

This parameters has been added to better understand systemic glycolysis in this population in the context of measuring bioenergetics in muscle via fMRS. Normal LDH levels in children vary by age. Normal adult range is 140-280 U/L. An elevated level of lactate dehydrogenase (LDH) in glycolysis indicates an increased rate of anaerobic metabolism.

Trough risdiplam drug level is measured in nanograms per milliliter from blood samples and indicates the concentration of risdiplam in someone's blood stream. Higher values mean someone has more risdiplam exposure.

This will only be tested on participants who are taking the drug risdiplam.

The Pediatric Quality of Life Inventory (PedsQL) is a 23-item questionnaire measuring health-related quality of life in children and adolescents aged 2-18. Higher scores indicate better quality of life.

The Pediatric Outcomes Data Collection Instrument (PODCI) is an 83-86 item questionnaire that measures the health-related quality of life for children and adolescents with musculoskeletal disorders aged 2-18. Higher scores indicate better quality of life.

The SMA Health Index (SMA-HI) is a 107 item questionnaire that measures a patient's perception of disease burden in 15 areas of health related to SMA. Higher scores indicate more SMA disease burden