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

Esmee S B van Kleef; Karlijn Bouman; Joery P F Molenaar; Benno Küsters; Jan T Groothuis; Montse Olivé; Edoardo Malfatti; Erik-Jan Kamsteeg; Baziel G M Van Engelen; Coen A C Ottenheijm; Jonne Doorduin; Nicol C Voermans

doi:10.1212/NXG.0000000000200214

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

Neurol Genet. 2024 Dec 5;10(6):e200214. doi: 10.1212/NXG.0000000000200214. eCollection 2024 Dec.

Affiliation

¹ From the Department of Neurology (E.S.B.K., K.B., J.P.F.M., B.G.M.V.E., J.D., N.C.V.), Donders Institute for Brain, Cognition and Behaviour; Department of Pathology (B.K.); Department of Rehabilitation (J.T.G.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Neuromuscular Diseases Unit (M.O.), Department of Neurology, Hospital de La Santa Creu i Sant Pau; Biomedical Research Institute Sant Pau (IIB Sant Pau) Spain; Centro para la Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona; Univ Paris Est Créteil (E.M.), INSERM, U955 IMRB; AP-HP, Hopital Mondor, Neuromuscular Reference Center, Créteil, France; Department of Human Genetics (E.-J.K.), Radboud University Medical Center; and Department of Physiology (C.A.C.O.), Amsterdam University Medical Centers, the Netherlands.

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.