Paramyotonia congenita
Encyclopedia
Paramyotonia Congenita also known as Paramyotonia congenita of von Eulenburg or Eulenburg disease, is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia
. This type of myotonia
has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita
, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders
, patients with PC may also have potassium provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis
and there is debate as to whether the two disorders are actually distinct.
. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia and/or weakness. Typical presentations of this are during squating or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrot
s and watermelon
are able to induce these symptoms. The canonical definition of this disorder precludes permanent weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature.
may be used to distinguish between paramyotonia congenita and myotonia congenita., Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis
, or one of the potassium-aggravated myotonia
s. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.
and the potassium-aggravated myotonia
s) is caused by mutations in a sodium channel, SCN4A
. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1.
There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations.
population. Here, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). It should be noted, however, that the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect
is seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%.
Myotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
. This type of myotonia
Myotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita
Myotonia congenita
Congenital myotonia is a genetic, neuromuscular channelopathy that affects skeletal muscles . It is congenital, meaning that it is present from birth. Amongst other problems, it causes delayed relaxation of the muscles and rigidity...
, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders
Periodic paralysis
Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind...
, patients with PC may also have potassium provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
and there is debate as to whether the two disorders are actually distinct.
Symptoms and signs
Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked-off, in contrast to myotonia congenitaMyotonia congenita
Congenital myotonia is a genetic, neuromuscular channelopathy that affects skeletal muscles . It is congenital, meaning that it is present from birth. Amongst other problems, it causes delayed relaxation of the muscles and rigidity...
. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia and/or weakness. Typical presentations of this are during squating or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrot
Carrot
The carrot is a root vegetable, usually orange in colour, though purple, red, white, and yellow varieties exist. It has a crisp texture when fresh...
s and watermelon
Watermelon
Watermelon is a vine-like flowering plant originally from southern Africa. Its fruit, which is also called watermelon, is a special kind referred to by botanists as a pepo, a berry which has a thick rind and fleshy center...
are able to induce these symptoms. The canonical definition of this disorder precludes permanent weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature.
Diagnosis
Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise/movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. ElectromyographyElectromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
may be used to distinguish between paramyotonia congenita and myotonia congenita., Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
, or one of the potassium-aggravated myotonia
Potassium-aggravated myotonia
Potassium-aggravated myotonia is a rare genetic disorder that affects skeletal muscle. Beginning in childhood or adolescence, people with this condition experience bouts of sustained muscle tensing that prevent muscles from relaxing normally...
s. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.
Pathophysiology
Paramyotonia congenita (as well as hyperkalemic periodic paralysisHyperkalemic periodic paralysis
Hyperkalemic periodic paralysis is a genetic disorder which occurs in both humans and horses, where it is also known as Impressive Syndrome. It is an inherited autosomal dominant disorder which affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood...
and the potassium-aggravated myotonia
Potassium-aggravated myotonia
Potassium-aggravated myotonia is a rare genetic disorder that affects skeletal muscle. Beginning in childhood or adolescence, people with this condition experience bouts of sustained muscle tensing that prevent muscles from relaxing normally...
s) is caused by mutations in a sodium channel, SCN4A
SCN4A
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.The Nav1.4 voltage-gated sodium channel is encoded by the gene...
. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1.
There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations.
Treatment/Management
Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others, however, require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of mytonia prevention.Epidemiology
Paramyotonia congenita is considered an extremely rare disorder, though little epidemiological work has been done. Prevalence is generally higher in European derived populations and lower among Asians. Epidemiological estimates have been provided for the GermanGermany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
population. Here, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). It should be noted, however, that the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
is seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%.
History
Originally thought to be separate from hyperkalemic periodic paralysis and the sodium channel myotonias, there is now considerable disagreement as to whether these disorders represent separate entities or overlapping phenotypes of a complex disorder spectrum.External links
- Paramyotonia congenita FAQ at the Periodic Paralysis News Desk. The site also hosts a mailing list for patients with the disorder and medical professionals interested in it.
- Fact page from the Muscular Dystrophy Association