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Disease Definitions - For Physicians

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Andersen-Tawil Syndrome (ATS)

Patients with ATS typically present with the triad of potassium-sensitive periodic paralysis without myotonia, cardiac arrhythmias, and developmental dysmorphisms. Periodic paralysis is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk) due to hypoexcitability of muscle membranes. The dysmorphisms described include: hypertelorism, broad nasal root, mandibular hypoplasia, low-set ears, scaphocephaly, syndactyly and clinodactyly V, as well as a defect of the soft and hard palate. Dysmorphic features are most often mild and nondisfiguring, and are easily overlooked on routine physical examination. Age of onset of periodic paralysis ranges from 4 to 18 years. Rest following physical exertion is a common trigger, as in the classic forms of periodic paralysis.

Mutations in KCNJ2 - the gene encoding the inward-rectifying K+ channel Kir2 are the primary cause of ATS with 21 mutations discovered in 30 families. Mutations in KCNJ2 are the primary cause of ATS with 21 mutations discovered in 30 families. These mutations affect channel function through heterogeneous mechanisms, including reduced PIP2-related channel activation and altered pore function. Aside from KCNJ2-based ATS, the genetic basis of this disease in nearly 40% of cases is unknown. Other ATS genes likely share a common pathway or function with Kir2.1 or facilitate the activity of this ion channel.

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Episodic Ataxias

Episodic Ataxia Type 1 (EA1) (OMIM 160120)
EA1
, also called ataxia with myokymia, is an autosomal dominant disorder characterized by brief attacks (<15 min) of ataxia and dysarthria that can occur up to 15 times per day. Attacks can occur spontaneously or can be triggered by anxiety, exercise, startle, and intercurrent illness. Onset is typically in late childhood and early adolescence; symptoms usually remit in the second decade. Between attacks, widespread myokymia of the face, hands, arms, and legs occurs Electromyographic studies reveal myokymia (neuromyotonia). Phenytoin can control symptoms; acetazolamide is also effective. It is associated with mutations in the potassium channel gene KCNA1, which have been mapped to chromosome12p13.

Episodic Ataxia Type 2 (EA2) (OMIM 108500)
EA2 is an autosomal dominant disorder, which typically starts in childhood or early adolescence (range two years to 32 years). EA2 is characterized by paroxysmal attacks of ataxia, vertigo, and nausea that typically last hours to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. About 50% of patients with EA2 have migraine headaches. Frequency of attacks can range from once or twice a year to three or four times a week. Attacks can be triggered by stress, exertion, caffeine, alcohol, and phenytoin. Attacks can be stopped or decreased in frequency and severity by administration of acetazolamide. Between attacks, patients may initially be asymptomatic but eventually develop interictal findings that can include nystagmus and ataxia.

The genes CACNA1A (chromosomal locus 19p13) and CACNB4 (chromosomal locus 2q22-q23) are known to be associated with EA2. CACNA1A and CACNB4 molecular genetic testing is available on a research basis only.

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Non-dystrophic Myotonic Disorders

Myotonia Congenita
Myotonia is delayed relaxation of muscle fibers after voluntary contractions or mechanical stimulation. The myotonia results from hyperexcitability of the skeletal muscle membrane. It is manifested as spontaneous repetitive electrical activity of the skeletal muscle membrane, which can be recorded as ‘myotonic runs’ on electromyography (EMG). Clinically, patients with myotonia show muscle stiffness.

Myotonia congenita (MC) is an inherited muscle disorder whose main manifestation is myotonia. The worldwide prevalence of MC is about 1/100 000. MC can be inherited either as an autosomal dominant (Thomsen's myotonia, OMIM 160800) or an autosomal recessive (Becker's myotonia, OMIM 255700) trait. Both disorders are characterized by myotonia and muscular hypertrophy, but the latter is clinically more severe and more frequent. In MC patients, the muscle stiffness is usually most pronounced in the extremities, particularly during rapid voluntary muscle movements initiated after a period of rest. The clinical classification as Thomsen's or Becker's myotonia has been based mainly on the inheritance pattern shown in the families. Thomsen's and Becker's myotonia have both been shown to be associated with mutations in the skeletal muscle chloride channel gene, CLCN1, which encodes the major skeletal muscle chloride channel, ClC- 1. CLCN1 maps to chromosome 7q35, and is organized in 23 exons. So far, at least 50 CLCN1 mutations, comprising missense and nonsense mutations, insertions and deletions as well as splice mutations, have been identified in MC patients. Five mutations (G200R, V286A, I290M, F307S, and P480L) have been reported in association with Thomsen's myotonia, six mutations (G230E, A313T, R338Q, Q552R, I556N, and R894X) can cause both types of myotonia, and the remaining majority results in Becker's myotonia. These mutations are distributed over the entire CLCN1 gene, showing no special patterns for mutations with a dominant or recessive inheritance.

Paramyotonia congenita (PMC) (OMIM #168300)
This disease is an autosomal dominant disorder with high penetrance characterized by (1) myotonia that paradoxically worsens with exercise “paramyotonia”, (2) myotonia increased by exposure to cold, (3) intermittent flaccid paralysis (4) absence of muscle hypertrophy or atrophy and (5) lability of serum potassium. Families have been described manifesting only with paramyotonia without cold paralysis.

PMC is associated with mutations in the SCNA4 gene. It has been suggested that these are temperature-sensitive mutations as at normal temperatures the mutations have minimal clinical significance, while a minimal drop in temperature may effect movement of the sodium channel loop enough to allow an abnormal sodium flux.

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