Non-dystrophic myotonia and periodic paralysis

The non-dystrophic myotonias and primary periodic paralyses affect almost exclusively skeletal muscle, without the relevant extra-muscular involvement characteristic of dystrophic myotonias. Onset typically falls within the first to second decade of life, with substantial heterogeneity across spectrum entities: hyperkalaemic periodic paralysis and autosomal dominant myotonia congenita (Thomsen disease) often begin in early childhood, whereas hypokalaemic periodic paralysis, normokalemic periodic paralysis, and Andersen-Tawil syndrome more commonly present in the late first or second decade. In the non-dystrophic myotonias the lead clinical feature is myotonia, frequently reported by affected individuals as stiffness on suddenly initiated movements after rest; muscle architecture is essentially preserved between episodes. In the primary periodic paralyses, transient flaccid weakness predominates, with attack frequency and duration modulated by exercise, rest after exertion, temperature, dietary potassium, and stress.

The estimated prevalence of myotonia congenita is approximately 1/100,000 worldwide, rising to approximately 1/10,000 in northern Scandinavia, with the primary periodic paralyses approximately tenfold rarer. Comparable figures derive from English and Dutch registry studies.

A small group of voltage-gated ion-channel genes (CLCN1, SCN4A, CACNA1S, KCNJ2) underlies non-dystrophic myotonia and periodic paralysis, grouped into non-dystrophic myotonias and primary periodic paralyses. CLCN1-associated myotonia congenita is the most frequent non-dystrophic myotonia; hypokalaemic periodic paralysis (CACNA1S, SCN4A) is the most common periodic paralysis. Andersen-Tawil syndrome (KCNJ2) adds extramuscular features.

Non-dystrophic myotonia and periodic paralysis follow heterogeneous inheritance patterns. Myotonia congenita occurs in both autosomal dominant (Thomsen) and autosomal recessive (Becker) forms, with autosomal recessive predominating (approximately 70%) in most molecularly confirmed cohorts. Paramyotonia congenita, sodium channel myotonia, hyperkalaemic and hypokalaemic periodic paralysis, and Andersen-Tawil syndrome are each inherited in an autosomal dominant manner.

• Where non-dystrophic myotonia or periodic paralysis is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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