Characterization of New Phenotypes of Patients With Spinal Muscular Atrophy Treated With SMN Restoring Therapy

Primary outcomes

1. Markers of disease progression and description of different phenotypes, at : muscular and functional

   Time frame: Every 6 months from inclusion (Day 0, Month6, Month12, Month18, Month24)

   A composite score indicating the overall motor development trajectory for patients from study inclusion to Month 24 (M24).

   Calculation: Assign numerical values or categories to represent the motor development stages, with higher scores indicating positive development and lower scores indicating decline.

2. Markers of disease progression and description of different phenotypes, at : muscular and functional

   Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)

   The trajectory of mean scores for motor function and muscle strength measured using CHOP-INTEND for patients aged 0-2 years. Scores are assessed every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24).

   Scale: CHOP-INTEND scale (0-64) Minimum Value: 0 Maximum Value: 64 Interpretation: Higher scores indicate improved motor function and muscle strength.

3. Markers of disease progression and description of different phenotypes, at : muscular and functional

   Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)

   Motor Function Measure 32 (MFM-32), is a quantitative scale created to measure global motor functional abilities in a person with neuromuscular disease. It contains 32 items, each marked from 0 to 3. The total score and the sub-scores are expressed as a percentage of the maximum possible score.

   Scale Range: 0 to 100 (Minimum to Maximum Values)

   Interpretation: Higher scores on the Motor Function Measure 32 (MFM-32) indicate improved motor function and muscle strength.

   The lower the total score, the more severe the impairment.

4. Markers of disease progression and description of different phenotypes, at : muscular and functional

   Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)

   Motor function and muscle strength: Trajectory of mean score between inclusion and M24: 6-minute walk test (≥ 6 years walking)

5. Markers of disease progression and description of different phenotypes, at : muscular and functional

   Time frame: Every 6 months from inclusion (Day 0, Month 6, Month 12, Month 18, Month 24)

   Motor function and muscle strength: Trajectory of mean score between inclusion and M24:

   Myogrip (≥ 6 years), Myopinch (≥ 6 years)

6. Markers of disease progression and description of different phenotypes, at : Fatigue

   Time frame: Syde: At Day 0, Month 6, Month 12 and Month 24

   For All:

   Upper limb kinematics and power

   For Walkers:

   Gait variables, arm swing variables, walking perimeter Interpretation: Specific statistical quantities related to upper limb kinematics and power, and additional variables for walkers.

   Calculation: Analyze statistical quantities at each time point for Syde

7. Markers of disease progression and description of different phenotypes, at : Fatigue

   Time frame: Endurance test (≥ 6 years)

   Endurance time from 0 to 1200 The primary outcome measure for fatigue-related markers involves the endurance test (≥ 6 years), specifically assessing ESNHPT, ESBBT, and ESWT. The primary focus is on the proportion of patients who stop before completing the test (yes/no) and, if applicable, the mean time to stop in seconds.

   ESNHPT: Endurance Test - Non-Handheld Propulsion Task ESBBT: Endurance Test - Bodyweight Bearing Task ESWT: Endurance Test - Walking Task

8. Markers of disease progression and description of different phenotypes, at : Fatigue

   Time frame: at Day 0, Month 12 and Month 24

   Pediatric Quality of Life Inventory (PedsQL) Fatigue Total Score Minimum Value: 0 Maximum Value: 24 Interpretation: A higher score within the range indicates increased fatigue, while a lower score suggests less fatigue.

9. Markers of disease progression and description of different phenotypes, at Orthopaedic level

   Time frame: Joint amplitudes at Day 0, Month 6, Month 12 and Month 24

   Joint amplitudes: Trajectory of joint amplitude changes (angle) between Day 0 and Month 24 for each location:

   Hip (right and left), Knee (right and left), Ankles, Elbow, Wrist, Long fingers.

10. Markers of disease progression and description of different phenotypes, at Orthopaedic level

    Time frame: Clinic and spinal radiography at Day 0, Month 12,Month 18, Month 24

    (For Non-Operated Patients): Presence or Absence of Radiological Scoliosis

11. Markers of disease progression and description of different phenotypes, at Orthopaedic level

    Time frame: at Day 0, Month 24+/- Month 6, Month 12, Month 18

    Clinical and pelvic radiography:

    Proportion of patients with hip eccentricity (>10% on Reimers index) at Day 0 and Month 24

12. Markers of disease progression and description of different phenotypes, at the cognitive level: Vineland-II

    Time frame: At Month 1

    Vineland II Adaptive Behaviour scales (VABS) total mean score and subscale mean scores.

    Standardized questionnaire filled by the Neupsy during an interview with the parents or the patient himself if possible. 5 domains. Maximum score 160, minimum score 20, mean score 100, standard deviation 15

13. Markers of disease progression and description of different phenotypes, at the cognitive level: Bayley-4

    Time frame: At Day 0 and Month 18

    Bayley-4 Scales of Infant and Toddler Development is standardized developmental assessment tool for determining a child's developmental status at a given age (up to 42 months) BAYLEY-4 assess development in children of 1-42 months old in 5 domains: cognition, motor, language, socio-emotional, and adaptive behavior.

    The Bayley-4 raw scores from 0-84 for the receptive communication subtest, 0-74 for the expressive communication subtest a higher score denotes a better outcome. The Bayley-4 standard score norms are converted to percentiles from <0.1 to >99.9 for the language

14. Markers of disease progression and description of different phenotypes, at the cognitive level: BRIEF (Behavioral Rating Inventory of Executive Function)

    Time frame: At Day 0 and Month 18

    BRIEF provides scores that are used to evaluate different aspects of executive function. The scores are typically presented in various subscales, each focusing on a specific domain of executive function.

    composite T-score for overall developmental function equal to or greater than 65 (-1.5 SD)

    The " composite T-score for overall developmental function equal to or greater than 65 (-1.5 SD)" indicates that a T-score composite for the overall developmental function is considered elevated or clinically significant if it equals or exceeds 65, which is 1.5 standard deviations above the mean in a standardized population. Higher scores on the BRIEF suggest greater difficulties in executive functioning, with a T-score of 65 or above indicating a higher level of impairment or challenges in this domain.

15. Markers of disease progression and description of different phenotypes, at the cognitive level: Conners-3

    Time frame: At Day 0 and Month 18

    • CONNERS-3 : 108-item hetero-questionnaire to assess the presence of symptoms of inattention, hyperactivity, impulsivity and other frequently associated disorders in children and adolescents aged 6 to 18. Symptoms are rated on a Likert scale with severity ratings from 0 (not at all/never) to 3 (very much/ very frequently). The Conners t-score range from 0 - 100. The higher the number, the worse the outcome

16. Markers of disease progression and description of different phenotypes, at the cognitive level: CELF-5 (Language and communication assessment battery)

    Time frame: At Day 0 and Month 18

    Standard Score: This score are derived from the total raw scores for each test and are on a normalized score scale that has a mean of 10 and a standard deviation (SD) of 3

    The mean score is 100, with a standard deviation of 15, meaning:

    that standard scores between 85-115 are within the normal range. Score Mild: 70-85, Moderate: 55-70, Severe: 55 and lower

17. Markers of disease progression and description of different phenotypes, at the cognitive level: EQ (Empathy quotient), AQ (Autism Quotient)

    Time frame: At Day 0 and Month 18

    Evaluation of the French Version of Screening Questionnaires for Autism and Asperger Syndrome: Autism Spectrum Quotient (AQ) Empathy Quotient (EQ) EQ is a 40-item questionnaire designed to measure empathy for patients aged 11 and above. The maximum score for this questionnaire is 80.

    Threshold score: ↓30 . Scores of 30 or less indicate a lack of empathy common in people with Autism.

    AQ comprises 50 questions, with 5 groups of 10 questions assessing imagination, social skills, attention switching, attention to detail and communication skills. Each of these items scores 1 point if the respondent records abnormal or autistic like behaviour. The minimum score on the AQ is 0 and the maximum 50 with high scores indicating high autistic traits.

18. Markers of disease progression and description of different phenotypes, at the cognitive level: M-CHAT-R (Modified Checklist for Autism in Toddlers)

    Time frame: At Day 0 and Month 18

    The Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) is a screener that will ask a series of 20 questions about the child's behavior.

    To score the M-CHAT-R, we add up the number of at-risk responses, and follow the algorithm below:

    LOW RISK:

    Total score between 0 and 2

    MEDIUM RISK:

    Total score between 3 and 7

    HIGH RISK:

    Total score between 8 and 20

19. Markers of disease progression and description of different phenotypes, at the cognitive level: SRS-2 (Social Responsiveness Scale, Second Edition)

    Time frame: At Day 0 and Month 18

    SRS measures social ability of children from 2 years to 18 years old. It is used primarily with individuals with Autism Spectrum Disorder (ASD), family members of individuals with ASD, and others who have social impairments. Parent or teacher questionnaire (65 items on a 4-point Likert scale). High scores are associated with more severe social impairments.

    Raw total scores are converted to gender-normed T scores

    SRS-2 total T-scoring:

    • Less than or equal to 59 = Within normal limits (generally not associated with ASD)
    • Between 60-65 = Mild range
    • Between 66-75 = Moderate range
    • Greater than or equal to 76 = Severe range (strongly associated with clinical diagnosis of ASD)

20. Markers of disease progression and description of different phenotypes, at the cognitive level: PVSE (Basic visuo-spatial perception)

    Time frame: At Day 0 and Month 18

    • Proportion of patients with overall score:

    • < OL_inf
    • OL_inf ≤ x < Q1
    • Q1 ≤ x < M
    • M ≤ x < Q3
    • Q3 ≤ x < Q3
    • ≥ OL sup

21. Markers of disease progression and description of different phenotypes, at the brain level

    Time frame: At Day 0

    Cerebral MRI :

    Proportion of patients with :

    • Posterior fossa anomaly
    • Midline anomaly
    • White matter anomaly
    • Cortical anomaly
    • Basal ganglia anomaly
    • Ventricular system anomaly
    • Pericerebral space abnormality
    • Brain MRI abnormality (including above variables)

22. Markers of disease progression and description of different phenotypes, at Cardiology level

    Time frame: At Day 0 +/- Month 12, Month 24

    Electrocardiogram (ECG): An abnormal ECG, with proportion for each type of abnormality Holter-ECG: An abnormal Holter-ECG, with proportion for each type of abnormality Echocardiography (only if troponin anomaly): Abnormal echocardiography, with proportions for each type of abnormality

23. Markers of disease progression and description of different phenotypes, at metabolic level : Anthropometric measurement trends

    Time frame: Anthropometric measurements at Day 0, Month 6, Month 12, Month 18, Month 24

    Anthropometric measurements may be used to monitor growth and nutritional status.

    Outcome of tracking these measurements could be the identification of trends related to weight gain and muscle mass development. Assessing changes in weight and body composition over time can provide valuable insights into the impact of SMA on physical development, guide nutritional interventions, and help healthcare providers tailor supportive care to address the unique needs of children with SMA

24. Markers of disease progression and description of different phenotypes, at metabolic level :

    Time frame: Food survey at Month 6, Month 24

    Food survey: average food intake

25. Markers of disease progression and description of different phenotypes, at metabolic level : fractures

    Time frame: at Day 0, Month 6, Month 12, Month 18, Month 24

    Number of fractures by location and mechanism

26. Markers of disease progression and description of different phenotypes, at metabolic level : renal ultrasound

    Time frame: at Month 6

    Proportion of patients with abnormal renal ultrasound

27. Markers of disease progression and description of different phenotypes, at metabolic level : Absorptiometry (DXA)

    Time frame: at Month 6

    DXA measurement will be performed to assess patient's body composition.

    Average values + SD (Standard Deviation):

    Lean mass and fat mass (kg) with deficit or excess of lean mass and fat mass (%) Total bone mineral content (g) Bone mineral density (z-score) at the spine, femoral neck, and distal femur

28. Markers of disease progression and description of different phenotypes, at metabolic level: Calorimetry

    Time frame: at Month 6

    Potential outcome of using this device is the accurate measurement of Resting Energy Expenditure (REE). This information can be particularly important in managing the nutritional needs of individuals with SMA, helping healthcare providers optimize dietary plans to meet the specific energy requirements of patients dealing with this neuromuscular disorder. Resting Energy Expenditure (REE).

29. Markers of disease progression and description of different phenotypes, at metabolic level : Impedancemetry

    Time frame: at Month 6 and Month 24

    Average +SD values of Impedancemetry results

30. Markers of disease progression and description of different phenotypes, at metabolic level : Fibroscan

    Time frame: At Month 6 and Month 24

    The FibroScan result is reported in kilopascals (kPa), representing the liver stiffness. The numerical value indicates the degree of stiffness, which correlates with the extent of liver fibrosis. The interpretation of the FibroScan score is as follows:

    Low Stiffness (Low kPa): Indicates a healthier, less fibrotic liver.

    Intermediate Stiffness: May suggest some degree of fibrosis, and further evaluation may be needed to determine the extent.

    High Stiffness (High kPa): Indicates more advanced liver fibrosis or cirrhosis.

31. Markers of disease progression and description of different phenotypes, at biological analysis

    Time frame: At Day 0, Month 6, Month 12, Month 18, Month 24

    Proportion of patients with biological abnormalities for each parameter:

    Blood/platelet count: Hb, leukocytes, platelets, ASAT, ALAT, GGT, PAL, TP, Sodium, potassium, bicarbonates, calcium, phosphorus, creatinine, glucose, proteins, urea, cystatin C, Troponin, BNP, NT-pro-BNP, Iron, Ferritin, copper, zinc, selenium, magnesium, Vitamins A,C,D,E, B12, Folates, Albumin, prealbumin, retinol-binding protein, ultra-sensitive C-reactive protein (CRP), FibroTest, PTH (parathormone) For these patients : % above normal

    • above
    • or below

32. Markers of disease progression and description of different phenotypes, at In terms of quality of life and autonomy

    Time frame: PedsQL family impact at Day 0, Month 12, Month 24

    Score evolution trajectory :

    PedsQL (Pediatric Quality of Life Inventory™) family impact The 36-item PedsQL™ Family Impact Module Scales encompass 6 scales measuring parent self-reported functioning: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 3) Social Functioning (4 items), 4) Cognitive Functioning (5 items), 5) Communication (3 items), 6) Worry (5 items), and 2 scales measuring parent-reported family functioning; 7) Daily Activities (3 items) and 8) Family Relationships (5 items).

    Scale Scores are computed as the sum of the items divided by the number of items answered.

    higher scores indicate better functioning (less negative impact)

33. Markers of disease progression and description of different phenotypes, at In terms of quality of life and autonomy

    Time frame: HUI-2, generic PedsQL and neuromuscular module at Day 0, Month 6, Month 12, Month 18 and Month 24

    HUI2 classification system consists of attributes (domains) of health to 6 levels of functional ability/disability within each attribute. For each attribute, singleattribute utility functions range from 0.00 for highly disabled (deaf) to 1.00 Score total : 0 - 1

34. Markers of disease progression and description of different phenotypes, at respiratory level : Chest/head circumference ratio (PT/PC ratio) (up to 3 years)

    Time frame: at Day 0, Month 6, Month 12, Month 18 and Month 24

    Outcome measure related to hospitalizations in the context is "Proportion of Patients with Escalation of Respiratory Assistance." This measure assesses the percentage of patients who experienced an escalation in respiratory support during their hospital stay, encompassing variables such as increased settings on home machines, use of resuscitative NIV, or intubation. This outcome provides critical insights into the respiratory management and support needs of patients during their hospitalizations.

35. Markers of disease progression and description of different phenotypes, at respiratory level : Chest/head circumference ratio (PT/PC ratio)

    Time frame: at Day 0, Month 6, Month 12, Month 18 and Month 24

    Evolution of the PT/PC ratio trajectory

36. Markers of disease progression and description of different phenotypes, at respiratory level : O2 saturation and nocturnal TcPCO2

    Time frame: at Day 0, Month 12, Month 24

    Evolution trajectory: This measure focuses on the percentage of children experiencing elevated levels of transcutaneous carbon dioxide (TcPCO2), specifically defined as time spent with TcPCO2 levels exceeding 50mmHg. This outcome is crucial in assessing the severity of respiratory compromise and may guide interventions to address and manage hypercapnia in the pediatric population.

37. Markers of disease progression and description of different phenotypes, at respiratory level: Respiratory function tests (≥ 6 years)

    Time frame: at Day 0, Month 12, Month 24

    Evolutionary trajectory: Evolution of Inspiratory Vital Capacity in Different Positions (% of Theoretical). This measure assesses changes over time in the percentage of theoretical inspiratory vital capacity achieved while standing or sitting and while lying down. This outcome provides valuable information about respiratory muscle function and potential changes in the ability to generate inspiratory volumes in different body positions.

38. Markers of disease progression at respiratory level

    Time frame: points (Day 0, between Day 0-Month 12, between Month 12 and Month 24)

    Evolutionary trajectory :

    Proportion of patients with central sleep apnea syndrome Proportion of patients with obstructive sleep apnea syndrome Proportion of patients with alveolar hypoventilation syndrome

39. Markers of disease progression and description of different phenotypes, at bulbar level (Evaluation of dysphagia and dysarthria): DDD-pNMD (Diagnostic list for Dysphagia and Dysarthria in pediatric NeuroMuscular Disorders)

    Time frame: At Day 0, Month 6, Month 12, Month 18, Month 24

    The DDD-pNMD is a scale where items are scored by a Speech-Language Therapist (SLT) on a 4-point scale, ranging from 0 (normal) to 3 (severe problems/impossible). The scale is designed to assess various aspects of swallowing and speech in children with neurological conditions.

    The DDD-pNMD screening is positive if score greater than or equal to 1.

40. Markers of disease progression and description of different phenotypes, at bulbar level (Evaluation of dysphagia and dysarthria): NdSSS (Neuromuscular Disease Swallowing Status Scale).

    Time frame: At Day 0, Month 6, Month 12, Month 18, Month 24

    An 8-stage Neuromuscular Disease Swallowing Status Scale (NdSSS) Positive if the level on the NdSSS scale is less than or equal to 7

41. Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: age of patient

    Time frame: At Day 0

    + SD: Age, age of onset of symptoms, age at start of treatment

42. Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion : patient gender

    Time frame: At Day 0

    Proportion of male patients

43. Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: SMA TYPE

    Time frame: At Day 0

    Proportion of patients by type of SMA (1, 2, 3) and by treatment

44. Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: number of copy

    Time frame: At Day 0

    SMN2 copy number distribution

45. Markers of disease progression and description of different phenotypes, at the level of Characteristics at inclusion: treatment

    Time frame: At Day 0

    Calculate the proportion of patients who underwent treatment changes, expressed as a percentage of the total study population.This measure provides insights into the adaptability and potential issues with the current therapeutic approach or side effects.

    A higher proportion of treatment changes may prompt further investigation and adjustments in treatment protocols, aiming to enhance overall patient outcomes.

    This focused outcome measure aims to capture the essence of treatment dynamics within the SMA patient population.