A Cross-Sectional Study of Nemaline Myopathy

Abstract

Objective: Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures.

Methods: Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments.

Results: The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease.

Conclusion: We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials.

Figure 1. General Cohort Characteristics

(A) Study cohort characteristics. There were 2 entry points into the study (2009 and 2016 family conferences). Sixteen individuals were assessed at both time points. (B) Genotype breakdown of the study cohort (n = 57). (C) Clinical classification of the study cohort. Two participants classified as “other: cardiomyopathy” were are not included. (D) Severity of disease as assessed by feeding, respiratory support, and motor function. Feeding was divided into oral feeding vs exclusively gastrostomy tube (G-tube) fed. Walking was defined as able to walk 10 ft. Standing and sitting were defined as able to stand/sit unassisted for 10 seconds. Four participants were excluded from calculations of highest motor function because they were ≤2 years old at the time of survey. Invasive support includes tracheostomy; noninvasive support includes mechanical ventilation mask, bilevel positive airway pressure machine, and continuous positive airway pressure machine. ^a age at study entry unknown for one participant.

Figure 2. Motor Function Evaluation

(A) Median Medical Research Council (MRC) scores for nemaline myopathy study cohort. This information was collected on 51 participants from both the 2009 and 2016 cohorts. The most recent MRC score was used for the individuals who participated at both time points. Hip flexion values were excluded from the figure because they could not be displayed in the diagram. Median MRC score for this muscle was 3 with a total of 31 participants assessed. (B) Goniometric scores were categorized for the elbows, knees, and ankles (n = 38). Grade 0 = no contracture/hyperflexibility with increasing joint restriction; grade 4 = most severe contracture. There was no difference between right and left sides; therefore, only the right side is presented in the figure.

Figure 3. Quantitative Motor Measurements

(A) Timed motor assessments in the study cohort. Reference values for healthy individuals were adapted from Pereira et al. (B) Gowers maneuver was assessed in 44 participants. Assisted Gowers: requires furniture for assistance in rising from supine to full upright posture; full Gowers: rolls over, stands up with both hands “climbing up” the legs to above the knees to achieve full upright posture; and half Gowers: rolls over, stands up with 1 hand support on lower legs. (C) Motor Functions Measure 20 (MFM20) scores (total and domain 1 [standing and transfers] of MFM20 [D1]) color coded by genotype. Max = maximum; NR = no reference values found; 10MRT = 10-m run time.

Figure 4. Pulmonary Function Measurements and Bulbar Function

(A) Summary of pulmonary function test (PFT) assessments in nemaline myopathy study cohort compared to reference values (n = 27) (Quanjer et al., Verma et al., Bianchi and Baiardi). (B) Drooling Rating Scale: frequency. (C) Drooling Rating Scale: severity. (D) Slurp test was assessed in 23 participants with reference values (Hudspeth et al.). FVC = forced vital capacity; MEP = maximum inspiratory and expiratory pressures; MIP = maximal inspiratory pressure; NR = no reference values available; PCF = peak cough flow.

Figure 5. Genotype-Phenotype Correlations

(A) For participants who harbored a pathogenic variant in ACTA1 or NEB, specific technology supports are broken down by wheelchair dependence, feeding tube, and tracheostomy. (B and C) Breakdown of the extent of feeding support, respiratory support, and highest motor function at the time of most recent survey completion by genotype. Participants ≤2 years old were excluded from highest motor function calculations. Walking was defined as able to walk 10 ft. Sitting was defined as able to sit for 10 seconds. Invasive support includes tracheostomy; noninvasive support includes mechanical ventilation mask, bilevel positive airway pressure machine, and continuous positive airway pressure machine. G-tube = gastrostomy tube.