Nemaline Myopathy Type 6 Caused by Variants in the KBTBD13 Gene: A Cross-Sectional Study of 24 Patients

Abstract

Background and objectives: Nemaline myopathy type 6 (NEM6) is the most prevalent type of nemaline myopathy in the Netherlands. Because a detailed clinical characterization is not available yet, we here provide a detailed assessment of 24 patients.

Methods: In this cross-sectional study, we performed a full clinical assessment (medical history and neurologic examination) in patients with NEM6. Patient demographics, causative variants in the KBTBD13 gene, creatine kinase levels, and the results of previous muscle biopsies were collected. We evaluated experienced health-related quality of life, fatigue severity, prevalence of falls, balance control (Mini-Balance Evaluation Systems Test [Mini-BESTest]), functional motor score (Motor Function Measure [MFM]), and 6-minute walk distance. We used transcranial magnetic stimulation to assess muscle relaxation kinetics.

Results: Twenty-four patients were included (19 women [19-76 years]; 5 men [25-57 years]). Key patient-reported symptoms since childhood were muscle weakness (n = 23; 96%), slowness of movements (n = 23; 96%), and difficulties with running (n = 20; 83%). Axial, proximal, and distal muscles showed mild weakness in most patients. Health-related quality of life was significantly lower, and there was a significantly increased fatigue severity compared with controls. Prospectively, in a period of 100 days, 8 patients (33%) fell at least 1 time, of whom 5 patients (21%) fell 2 times or more. The median total score on the Mini-BESTest was 24 (21.0-26.0 [interquartile range]) of 28 and the median total percentage on the MFM was 91% (83.5-95.3), both considered to be mildly abnormal. The 6-minute walk distance was below the lower limit of normal in 4 patients (17%). All patients with NEM6 showed a markedly reduced muscle relaxation rate with a median of 6.5 [4.9-8.1] s^-1 (lower limit of normal is 10.1 s^-1).

Discussion: This cross-sectional study in patients with NEM6 shows a relatively mild clinical phenotype and mildly abnormal functional tests. However, patients report an important impact on the daily activities, which is illustrated by functional difficulties, reduced quality of life, increased fatigue severity, and increased prevalence of falls. This might be related to delayed muscle relaxation. This study provides a comprehensive overview of the clinical presentation and functional limitations in patients with NEM6.

Figure 1. Patient-Reported symptoms

The number of patients reporting this selection of symptoms in childhood or currently. Slowness of movements was defined as a slow motor response to sudden unexpected events and inability to perform rapid movements. Muscle stiffness was defined as a constant experienced stiffness in the muscles not influenced by external factors such as temperature.

Figure 2. MRC Scores, MFM Scores, and Normalized pRR

(A) The MRC sum scores of patients with NEM6. The dots represent individual patients and the black horizontal line the median. (B) The median MRC scores of individual muscles with a frontal and dorsal view. (C) MFM scores of the different domains. Domain 1: standing position and transfers. Domain 2: axial and proximal motor function. Domain 3: distal motor function. (D) Normalized pRR in the patients with NEM6. Three patients were not included because of a contraindication or home visits, and 2 patients were excluded because of a silent period <150 ms. The dotted horizontal line represents the lower limit of normal. MFM = Motor Function Measure; MRC = Medical Research Council; NEM6 = nemaline myopathy type 6; pRR = peak relaxation rate.