Clinical Manifestation of Nebulin-Associated Nemaline Myopathy

Abstract

Background and objectives: Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS).

Methods: Clinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions.

Results: Thirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (±12) years and a median of 17 (±11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia.

Discussion: NM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.

Figure 1. Demographics and Main Characteristics of the Cohort

Demographics table (A) with the main characteristics of the cohort and a pie chart (B) illustrating the need for support in the main involved domains (motor, respiratory, and bulbar). Only 36% of patients did not need interventional support in the respiratory, motor, or bulbar systems and 18% of them needed support in all 3 systems.

Figure 2. Triple Furrow Sign in Nemaline Myopathy Caused by NEB Variants

Pronounced tongue atrophy with the triple furrow sign in 4 patients in A, B, C, and D.

Figure 3. Association Between Tongue Atrophy and Swallow Function in NM-NEB Represented by NdSSS Scores

Box plot showing the comparison of the NdSSS scores and the presence of tongue atrophy. There was significant association between tongue atrophy and swallow function. Patients with a trophic tongue had the highest scores of NdSSS, followed by those with mild tongue atrophy and those with pronounced tongue atrophy, which presented with the lowest scores on the swallow scale.

Figure 4. General Characteristics of the Cohort

Finger contractures (A and B) were found in patients with NM-NEB. Scoliosis and thoracic deformities were present in most of the patients, but pectus carinatum and kyphoscoliosis (C) were found only in 2 siblings. (D) Prominent cervical flexor weakness in a patient with a childhood-onset form despite presenting with no facial or proximal weakness.

Figure 5. Ventilatory Support Characterization

(A) Main characteristics of patients who used ventilatory support vs those who did not use ventilatory support during evaluation. (B) Time-to-event analysis to the ventilatory support demonstrates that most of the patients start the ventilatory support before the age of 20 years and that, at approximately 40 years of age, less than 15% of the patients are not going to need ventilatory assistance. *In this analysis, we included only patients older than 3 years. **In this analysis, we excluded patients who were not accessed for tongue atrophy.

Figure 6. Progression of the Disease

Clinical manifestations separated by age groups. Bar plot showing patients categorized by age groups according to maximum motor function (A) type of ventilatory support (B), the presence of spine deformities (C) and the use of ventilatory support (D). This analysis showed stability of the disease in the bulbar and motor domains and a progressive course in the respiratory domain and among the skeletal deformities.