WiTNNess: An international natural history study of infantile-onset TNNT1 myopathy

Abstract

Objective: We created WiTNNess as a hybrid prospective/cross-sectional observational study to simulate a clinical trial for infantile-onset TNNT1 myopathy. Our aims were to identify populations for future trial enrollment, rehearse outcome assessments, specify endpoints, and refine trial logistics.

Methods: Eligible participants had biallelic pathogenic variants of TNNT1 and infantile-onset proximal weakness without confounding conditions. The primary endpoint was ventilator-free survival. "Thriving" was a secondary endpoint defined as the ability to swallow and grow normally without non-oral feeding support. Endpoints of gross motor function included independent sitting and standing as defined by the Word Health Organization, a novel TNNT1 abbreviated motor score, and video mapping of limb movement. We recorded adverse events, concomitant medications, and indices of organ function to serve as comparators of safety in future trials.

Results: Sixteen children were enrolled in the aggregate cohort (6 prospective, 10 cross-sectional; median census age 2.3 years, range 0.5-13.8). Median ventilator-free survival was 20.2 months and probability of death or permanent mechanical ventilation was 100% by age 60 months. All six children (100%) in the prospective arm failed to thrive by age 12 months. Only 2 of 16 (13%) children in the aggregate cohort sat independently and none stood alone. Novel exploratory motor assessments also proved informative. Laboratory and imaging data suggest that primary manifestations of TNNT1 deficiency are restricted to skeletal muscle.

Interpretation: WiTNNess allowed us to streamline and economize the collection of historical control data without compromising scientific rigor, and thereby establish a sound operational framework for future clinical trials.

Figure 1

Overview of WiTNNess outcomes. Each bar represents a child in the prospective (light gray, n = 6) or cross‐sectional (dark gray n = 10) arm. Bar length indicates census age (in years; upper border) and symbols show patient age at time of gastrostomy insertion (orange circles), tracheostomy insertion (red diamonds), independent sitting (white/black icons), or death (white/red crosses). The dashed blue vertical line (birth to age 2 years) marks the proposed time window for future clinical trials.

Figure 2

Primary endpoint: Ventilator‐free survival. (A) Median ventilator‐free survival was 20.2 months for children in the aggregate WiTNNess cohort (purple diamonds, n = 16) and longer than median ventilator‐free survival of 88 Amish children with TNNT1 myopathy ascertained retrospectively (18.3 months; gray dotted line). (B) This difference was explained by longer survival of children in the cross‐sectional (46.0 months; blue circles, n = 10) as compared to prospective (17.1 months; red line, n = 6) arm.

Figure 3

Mechanical life support. (A) For surviving children in the aggregate cohort, the probability of gastrostomy tube or tracheostomy tube insertion reached 100% by ages 45 and 60 months, respectively. (B) Gastrostomy feeding did not significantly prolong ventilator‐free survival.

Figure 4

Secondary endpoint: Thriving. “Thriving” was a secondary endpoint defined as the ability to maintain weight at ≥3rd WHO reference percentile for sex and age (gray shading) without non‐oral nutritional support (i.e., nasogastric or gastrostomy feeding). According to this definition, all six (100%) children in the prospective cohort failed to thrive by age 12 months. Each colored line represents a female (A) or male (B) child; asterisks and squares indicate the timing of death or gastrostomy insertion, respectively.

Figure 5

Secondary and exploratory motor outcomes. (A) Independent sitting for ≥10 s was achieved by 2 (13%) of 16 WiTNNess participants, shown as red circles (prospective cohort, n = 6) or diamonds (cross‐sectional cohort, n = 10). Both children who sat independently were from the cross‐sectional group, but statistically this outcome did not differ between cohorts (Mantel–Cox log‐rank: chi‐square = 0.97, p = 0.3248). For comparison, gray shading indicates the 1st–99th percentile reference window for this milestone (WHO‐MGRS), and the blue dashed line shows time to independent sitting for 56 normally developing Amish and Mennonite children. (B) No child in WiTNNess achieved independent standing. (C) The TNNT1 abbreviated motor scale (TAMS) characterized early motor development using 10 maneuvers adapted from the Neuromuscular Gross Motor Outcome Scale (maximum score of 20, gray dashed line). No child in WiTNNess achieved a TAMS score exceeding 12 at any time point (each line represents one child from the prospective cohort). (D) The Ability Captured Through Interactive Video Evaluation‐mini (ACTIVE‐mini) system recorded volume and speed of movement in all four limbs from supine position. Spontaneous limb movement was greater in arms (blue circles) as compared to legs (green diamonds) and became negligible after 24 months of age.

Figure 6

Biomarkers: Chest deformity and blood gases. (A) Lateral chest radiograph of a child with TNNT1 myopathy (right panel, age 12 months) compared to a healthy child (left panel, age 13 months) shows pectus carinatum (white arrowhead) and cephalocaudal shortening of the thoracic cavity (white arrows). (B) Posterior–anterior chest radiograph at an older age (right panel, 25 months) shows contracture of the intercostal spaces (asterisks), flattening of the thoracic contour (solid lines), and scoliosis (dashed line). (C) These anatomical changes were accompanied by progressive hypoxemia and hypercarbia in the months preceding death (asterisks).