A Likely Pathogenic variant in the KBTBD13 Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6

Author:

van Kleef Esmee S.B.1,Bouman Karlijn1,Molenaar Joery P.F.1,de Winter Josine M.2,Duijkers Floor A.M.3,Eftimov Filip4,Verschuuren-Bemelmans Corien C.5,van der Laan Tineke,Küsters Benno6,Malfatti Edoardo78,Kamsteeg Erik-Jan9,van Engelen Baziel G.M.1,Ottenheijm Coen A.C.2,Doorduin Jonne1,Voermans Nicol C.1

Affiliation:

1. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

2. Department of Physiology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands

3. Department of Human Genetics, Amsterdam UMC, University of Amsterdam, The Netherlands

4. Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands

5. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

6. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

7. Univ Paris Est Créteil, INSERM, U955 IMRB, Créteil, France

8. AP-HP, Hopital Mondor, Neuromuscular Reference Center, F-94010 Créteil, France

9. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

Abstract

Background: Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant. Objective: To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene. Results: We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier. Conclusions: The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.

Publisher

IOS Press

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