Titel thesis: Redefining the non-dystrophic myotonic syndromes.
Phenotypic characterisation based on genetic testing.
Chapter 1 gives a general introduction to non-dystrophic myotonic syndromes (NDMs). Chapter 2 comprises a systematic review about drug treatment for myotonia. Three small crossover studies evaluated myotonia in myotonic dystrophy. Unfortunately, for the treatment of myotonia in NDMs we were unable to find valid, separate data. Chapter 3 gives the outline of the thesis. In Chapter 4 we determined the genetic profiles of 54 probands by analysing CLCN1 and SCN4A in tandem. We established CLCN1 mutations in 32 families (59%) and SCN4A mutations in 22 families (41%), reflecting a high-level of mutation ascertainment. In Chapter 5 we describe three NDM patients with a genotype-phenotype mismatch. In Chapter 6 we redefine the non-dystrophic myotonic syndromes. Bedside tests revealed a higher incidence and longer relaxation times of myotonia in the leg muscles for chloride channelopathies and in eyelid muscles for the sodium channelopathies. Multivariate logistic regression analyses allowed us to develop clinical guidelines for genetic testing. Chapter 7 describes the health-status of patients with a NDM. Sixty-two patients, all off treatment, completed a standardised interview, the Fatigue Assessment Scale, and the 36-item Short-Form health survey. All physically oriented SF-36 domains were substantially lower in both channelopathy groups compared to the Dutch community scores. Fatigue proved to be the strongest predictor of low general-health perceptions, while painful myotonia best predicted low overall physical functioning. In Chapter 8 we systematically analysed the changes in and thickness of four limb muscles from genetically confirmed NDM patients by ultrasound. The results showed elevated echo intensities in all muscles except the rectus femoris, and hypertrophy in the arm muscles. In correlation with functional measurements these readings suggest structural muscle changes in NDMs. If muscle biopsies will also show structural changes, the designation non-dystrophic myotonic syndromes would be open to debate.
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