Paramyotonia Congenita
Paramyotonia congenita, also called Eulenburg disease, is a disease that affects muscle (skeletal muscle) movement. It usually occurs in childhood. The main symptom is muscle rigidity, which is often accompanied by muscle weakness, especially after exercise or cold. It usually lasts for several hours and cannot be relieved in time with rewarming. Some patients can also be induced in a hot environment. Muscle weakness can affect the whole body, or it can only affect local muscles. Percussive myotonia is easily seen in the tongue muscles, forearm muscles, thenar muscles and thigh muscles. The duration varies, and usually disappears after a few seconds. The patient is wide and short, and tends to be muscle hypertrophy, not as obvious as congenital myotonia. Studies show it is caused by a mutation in the skeletal muscle sodium channel (SCN4A) gene on chromosome 17, and Thr1313Met is the most common mutation. Unlike the tonic disease of the chloride channel, the muscle stiffness associated with PMC worsens rather than improves after exercise or repeated muscle contractions (paramuscular rigidity), and is extremely sensitive to cold, which is the opposite of the so-called warm-up phenomenon.
The disease common presents a benign process, and the condition becomes stable or improves after adults. A few may have persistent limb weakness and muscle atrophy. During the onset of the disease, the patient's blood K+ increased; blood Ca2+ decreased. EMG shows that the muscles have tonic discharge at room temperature. After continuous contraction, there is a slight post-release phenomenon when immediately relaxing. The myotonia discharge increased slightly after the cold water bath. Nerve repetitive stimulation examination the amplitude of stimulation above 10 Hz may decrease. When oral KCl makes blood K+ higher than 7 mmol/L, muscle rigidity and weakness can be induced.
Pathogenesis
Studies have found that the mutant SCN4A gene can cause congenital myotonia. This gene encodes a protein essential for the normal function of skeletal muscle cells. In order for the body to move normally, the skeletal muscles must be tense (contracted) and relaxed in a coordinated manner. Muscle contraction is triggered by the influx of positively charged atoms (ions) including sodium into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodiumions into these cells.
Figure 1.SCN4A mutations in congenital myopathy patients. (I. Zaharieva, et al.; 2016.)
Mutations in the SCN4A gene change the general structure and function of sodium channels. The altered channel cannot effectively regulate the flow of sodium ions into skeletal muscle cells. The resulting increase in ion current interferes with normal muscle contraction and relaxation, resulting in muscle stiffness and weakness.
Paramyotonia congenita is inherited in an autosomal dominant manner or sporadic. The mutation sites of SCN4A gene have been found: R672C, I693T, T704M, S804F, A1152D, A1156T, V1293I, G1306V, T1313A, T1313M, M1360V, M1370V, L1433R, etc. These mutations affect the rapid inactivation of the encoded sodium channels. There are also signs that some mutations cause changes to activate and inactivate. As a result of the changes in the dynamics of these channels, there is an extended inward (depolarizing) current after muscle stimulation. Due to the change in the voltage sensitivity of the channel dynamics, these lead to a general increase in cell excitability and cause muscle rigidity.
References
- Cavel-Greant D, et al. The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients. Acta Myol. 2012, 31(2):126-33.
- Finsterer J. Primary periodic paralyses. Acta Neurol Scand. 2008, 117(3):145-58.
- Magot A, et al. Focal and abnormally persistent paralysis associated with congenital paramyotonia. BMJ Case Rep. 2014, doi: 10.1136/bcr-2014-204430.
- I. Zaharieva, et al. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. BRAIN. 2016; 139: 674–691.
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