Clinical Features and Subclassification

DM1 is a multisystem, autosomal-dominantly inherited, highly variable muscle disease with an incidence of 1 in 8000 individuals (see Table 96-1) [Harper, 2001; Moxley and Meola, 2008]. Childhood-onset DM1 may present as a severe early congenital form, or as a milder form with symptoms beginning in the early school years. The congenital form presents at birth with respiratory failure, poor feeding, generalized hypotonia, clubfoot deformity, and an increased risk of intracerebral hemorrhage and eventration of the diaphragm [Harper, 2001]. During gestation, there are often reduced fetal movements and a history of polyhydramnios [Harper, 2001; Zaki et al., 2007]. There is an increased frequency of placenta previa and miscarriage [Harper, 2001; Rudnik-Schoneborn and Zerres, 2004; Rudnik-Schoneborn et al., 2006], and, not uncommonly, a failed labor may require urgent cesarean section. During the perinatal period, infants with congenital myotonic dystrophy may require continuous ventilator support, and those remaining ventilator-dependent beyond 4 weeks of age have a poor prognosis for survival, although recent advances in neonatal intensive care have allowed many affected infants to survive, with subsequent slow improvement in function throughout childhood and teens [Campbell et al., 2004; Harper, 2001]. During the first 2 years of life, children with congenital myotonic dystrophy are at increased risk for aspiration pneumonitis and difficulties with feeding. Mental retardation and learning disabilities are common in congenital myotonic dystrophy. Determining the degree of cognitive deficit requires careful evaluation because these patients have marked facial weakness and are unable to speak and communicate well until mid- to late childhood. There is also an increased incidence of hearing loss [Harper, 2001]. These problems often complicate neuropsychologic testing. Figure 96-1A shows a mother with two daughters, both of whom have congenital myotonic dystrophy. Both children have delayed ability to speak and cognitive impairment. Their mother has mild ptosis, minimal grip myotonia, and minimal distal weakness. She is fully employed and has no cognitive impairment. This mother has the classic adult-onset form of DM1 [Harper, 2001].

Fig. 96-1 Myotonic disorders.

A, Mother with mild to moderate myotonic dystrophy with her two children, both of whom have the congenital form of myotonic dystrophy. B, Father and son both have mutations in the gene for the skeletal muscle sodium channel and have the acetazolamide-responsive form of sodium channel myotonia (lower panel).

The later, childhood-onset form usually is evident from nonmuscular manifestations of the disease, such as intellectual deficiency, difficulty with speech or hearing, clumsiness, or, rarely, with a cardiac dysrhythmia or postoperative apnea [Harper, 2001; Sinclair and Reed, 2009]. DM1 patients may have an increased sensitivity to sedative medications, especially barbiturates and opiates. and occasionally experience increased muscle stiffness/myotonia during general anesthesia [Harper and van Engelen, 2004; Sinclair and Reed, 2009]. Cardiac arrhythmias are more common complications of the adult-onset forms of DM1 [Breton and Mathieu, 2009; Groh et al., 2008; Harper, 2001]. However, other nonmuscular manifestations, such as gastrointestinal hypomotility with chronic constipation, and intermittent urinary tract symptoms, such as urgency or frequent urination, are common in childhood myotonic dystrophy [Harper, 2001; Harper and van Engelen, 2004].

Genetics

DM1 results from an unstable trinucleotide expansion in the 3′ untranslated region of a gene on chromosome 19 that codes for a serine/threonine protein kinase, DMPK [Brook et al., 1992; Fu et al., 1992; Mahadevan et al., 1992]. The exact function of this kinase remains unclear. The cause of the unstable CTG repeat expansion also is unknown. Recent research suggests that premutations arise from the upper normal range of CTG repeat region sizes and become pathologically enlarged within a few generations [Abbruzzese et al., 2002; Martorell et al., 2001]. Past investigations demonstrate that mitomycin C can enhance enlargement of pathologically expanded repeats and promote enlargement of normal repeats [Pineiro et al., 2003]. Inhibitors of replication also modulate instability of the CTG repeat in the DM1 gene in cultured cells [Yang et al., 2003]. These observations raise the possibility that environmental/external factors may influence the development of pathologic enlargement of CTG repeats at the DM1 locus. Recent investigations suggest that DNA “repair” proteins may also have a mutagenic role in CTG repeat instability [Slean et al., 2008; Pearson et al., 2005]. The normal size of the [CTG]_n repeats ranges from 5 to 37 repeats. Children with the congenital form of DM1 have expansions typically greater than 1500 repeats [Harper, 2001]. Moderately affected adults with DM1 have [CTG]_n sizes ranging from 300 to 1000 repeats, and mildly affected individuals have expansions from 50 to 200 repeats. There are no examples of point mutations in the DMPK gene locus that have caused the clinical picture of DM1. The same is true for DM2.

The unstable expansion of the DM1 gene provides an explanation for the well-described phenomenon of anticipation: that is, the earlier onset of more severe manifestations of disease in successive generations. Figure 96-1 emphasizes the phenomenon of anticipation in the mother with mild to moderate DM1 has had two children with severe congenital DM1.

Pathophysiology

The likely molecular pathomechanism that underlies both DM1 and DM2 relates to the nuclear accumulation of RNA containing the abnormally expanded repeats (CUG in DM1 and CCUG in DM2). These accumulations of RNA are unable to exit from the nucleus and undergo normal removal [Osborne et al., 2009; Wheeler, 2008]. The abnormal accumulation of the expanded repeat-containing RNA alters the normal functions of specific nuclear regulatory proteins, such as muscleblind [Mankodi and Thornton, 2002; Mankodi et al., 2003] and CUGBP1 [Timchenko et al., 2002; Savkur et al., 2001; Charlet et al., 2002]. The net effect is a novel toxic RNA disease mechanism that causes abnormal splicing of pre-mRNA in both DM1 and DM2 [Osborne et al., 2009; Wheeler, 2008]. The toxic RNA hypothesis builds heavily upon studies of animal models, as well as on findings in human tissues. The normal DMPK gene contains a short CTG repeat in the 3′ untranslated region of exon 15, and expression of this gene produces an mRNA containing a short CUG repeat [Wheeler, 2008]. The normal zinc finger protein 9 gene (ZNF9 gene), which contains, in intron 1, a large CCTG expansion that is responsible for DM2 [Liquori et al., 2001], and normally contains a short CCTG repeat in intron 1, gives rise to a pre-mRNA containing a CCUG repeat [Wheeler, 2008]. Due to removal of the introns during the editing of pre-mRNA, the CCUG repeat tract is absent from the ZNF9 mRNA [Margolis et al., 2006]. In the presence of nonexpanded CUG and CCUG repeats, the activities of muscleblind nuclear regulatory protein 1 (MBNL1) and the CUGBP1 protein are normal [Wheeler, 2008]. This allows normal regulation of pre-mRNA splicing by these nuclear regulatory proteins and normal production of the proper proteins in the cell [Wheeler, 2008].

The misregulation that occurs in DM1 and DM2 causes a “spliceopathy” that affects at least two-dozen transcripts [Osborne et al., 2009; Wheeler, 2008]. Myotonia caused by a marked reduction in the synthesis of the adult form of the skeletal muscle chloride channel [Charlet et al., 2002; Mankodi et al., 2002], and insulin resistance caused by deficient synthesis of the adult form of the insulin receptor [Savkur et al., 2001, 2004] occur in DM1 and DM2 as a result of this splicing defect, and it is likely that additional disease manifestations result from this alteration. In DM1, not DM2, excess phosphorylation of CUGBP1 occurs and results in higher total levels of this protein, gain of function, and in turn perhaps leads to the more pronounced muscle wasting often seen in DM1 [Wheeler, 2008].

The cause of the muscle wasting and weakness in DM1 remains a mystery. In the transgenic mouse model developed by Mankodi and colleagues, the mice do not develop muscle wasting or significant weakness [Mankodi et al., 2000, 2002]. In DM1 patients, there are hormonal abnormalities, including testosterone deficiency, insulin resistance, hyperinsulinemia, and altered release of growth hormone, which may contribute to the muscle wasting. To date, however, therapeutic trials restoring or exceeding physiologic levels of these hormones have failed to reverse weakness and wasting [Harper, 2001; Moxley et al., 2004].

Recently, two new mouse models have been developed and provide encouraging new discoveries related to skeletal muscle wasting and cardiac disease in DM1. One study describes an inducible mouse model of severe skeletal muscle wasting that expresses large tracts of CTG repeats in DMPK exon 15 [Orengo et al., 2008]. The results indicate that increased CUGBP1 protein levels are associated with increased DMPK-CUG RNA expression, and suggest a role for CUGBP1-specific splicing or cytoplasmic functional alterations as causes of muscle wasting [Orengo et al., 2008]. The investigators found that pentamidine partially rescues the defect in splicing of two pre-mRNAs (the skeletal muscle chloride channel and Serca1 pre-mRNA) in this mouse model [Orengo et al., 2008], raising the possibility of future therapeutic trials with pentamidine.

Another recent study demonstrates that, in addition to the sequestration of MBNL1 by the toxic RNA CUG repeat tract in DM1, these expanded CUG tracts activate the protein kinase C (PKC) signaling pathway, which leads to hyperphosphorylation and stabilization of CUGBP1 in DM1 heart and skeletal muscle tissues [Wang et al., 2009]. This elevation of hyperphosphorylated CUGBP1 may have an important pathophysiological role in causing cardiac muscle dysfunction in DM1. To explore this possibility, the investigators used an inducible DM1 mouse model, in which a transgene containing the last exon of DMPK with 960 CTG repeats is induced to express CUG repeat-containing RNA [Wang et al., 2009]. These mice exhibited higher mortality, conduction abnormalities, and systolic and diastolic dysfunction, as well as molecular changes typical of patients with DM1. One group of these mice received PKC inhibitors and exhibited increased survival that correlated with decreased phosphorylation and decreased steady-state levels of CUGBP1. Treatment with PKC inhibitors also reduced misregulation of splicing that was normally regulated specifically by CUGBP1, but not those splicing events regulated by MBNL1 [Wang et al., 2009]. The investigators suggest that pharmacological blockade of PKC activity mitigates the DM1 cardiac phenotype and they propose that the PKC pathway plays an important role in the pathogenesis of DM1. More investigation is necessary to confirm and extend these findings.

Clinical Laboratory Tests

Identification of the abnormal expansion of [CTG]_n repeats in the DMPK gene on chromosome 19 establishes the diagnosis of DM1. Electromyography to detect myotonia is helpful in older children, but myotonia may be absent in infancy or in early childhood. Slit-lamp examination to identify the typical iridescent, spokelike posterior capsular cataracts is helpful. Muscle biopsy is not necessary to diagnose DM1 but may be useful to exclude other disorders. Careful examination of the mothers of patients with suspected congenital DM1 may reveal subtle clinical findings. Muscle pathology often demonstrates prominent central nuclei, scattered angular fibers, pyknotic nuclear clumps, and type 1 fiber atrophy. Creatine kinase levels may be normal or elevated and are not of primary value in the diagnosis [Heatwole et al., 2006]. With the discovery of the gene defect in DM1, it is possible to perform both prenatal and perinatal genetic counseling. Analysis of the DNA isolated from amniocytes or chorionic villus samples can predict the delivery of affected infants and the severity of illness [Harper, 2001; Harper and van Engelen, 2004].

Treatment

Treating patients with congenital myotonic dystrophy involves ventilatory support, use of a feeding tube, bracing for clubfoot deformities when present, and occasional corrective surgery for foot deformities (Figure 96-2) [Harper, 2001; Harper and van Engelen, 2004; Canavese and Sussman, 2009]. Figure 96-2 shows the molded plastic orthosis that helps treat foot deformity later in childhood. Speech problems and abdominal pain may improve with antimyotonia treatment. Mexiletine is sometimes helpful in alleviating some of the symptoms, especially in later childhood or adolescence when patients may have recurrent dislocation of the mandible, and pain and muscle spasm in the masseter muscles. Electrocardiographic monitoring is necessary on a regular basis, particularly during treatment with mexiletine, to search for covert dysrhythmias [Christensen et al., 2008; Otten et al., 2009; Gorog et al., 2005]. Treatment should be coordinated with the child’s school to ensure that cognitive deficiencies and hearing deficits are monitored. The increased risk for cardiac dysrhythmia and apnea after administration of general anesthesia for surgery requires overnight hospitalization with monitoring [White and Bass, 2003; Sinclair and Reed, 2009]. Apnea can develop several hours after a patient has been extubated [Harper and van Engelen, 2004]. No specific limitation on physical activity is necessary during childhood, provided the child has gained sufficient strength and coordination to carry out activities requested in the school environment.

Fig. 96-2 An example of the plastic molded foot orthosis that is useful in the treatment of clubfoot deformity in congenital myotonic dystrophy.

Clinical Features

DM2/PROMM typically appears in adult life and has variable manifestations, such as early-onset cataracts (younger than 50 years), varying grip myotonia, thigh muscle stiffness, and muscle pain, as well as weakness (hip flexors, hip extensors, abdominal muscles, or long flexors of the fingers) [Day et al., 2003; Moxley et al., 2002; Ricker et al., 1994a, 1995; Schoser et al., 2004b; Thornton et al., 1994]. Symptoms often appear between 20 and 70 years of age, and patients, as well as their care providers, ascribe them to overuse of muscles, “pinched nerves,” “sciatica,” arthritis, fibromyalgia, or statin use [George et al., 2004]. Younger patients may complain of stiffness or weakness when running up steps. In general, DM2 muscle pain has no consistent relationship to exercise or to the severity of myotonia found on clinical examination. The pain, which tends to come and go without obvious cause, usually fluctuates in intensity and distribution over the limbs. It can last for days to weeks. This pain seems qualitatively different from the muscle and musculoskeletal pain that occurs in patients with DM1.

Early in the presentation of DM2 there is only mild weakness of hip extension, thigh flexion, and finger flexion. Myotonia of grip and thigh muscle stiffness vary from minimal to moderate severity over days to weeks. Direct percussion of forearm extensor and thenar muscles is the most sensitive clinical test for myotonia in DM2 but may be absent. Myotonia of grip is sometimes prominent and often has a jerky quality that seems to differ from that in DM1 and the nondystrophic myotonias. Myotonia is often less apparent in DM2, compared to patients with DM1. In cases of late-onset DM2, myotonia may only appear on electromyographic testing after examination of several muscles [Day et al., 2003; Ricker et al., 1995]. Facial weakness is mild in DM2, as is muscle wasting in the face and limbs. Weakness of neck flexors is frequent. Trouble arising from a squat is common, especially as the disease progresses. Calf-muscle hypertrophy occasionally is prominent [Ricker et al., 1994a, 1995; Thornton et al., 1994]. Other manifestations, such as excessive sweating, hypogonadism, glucose intolerance, dysphagia, cardiac conduction disturbances, and cognitive/ neuropsychologic alterations, may also occur and worsen over time [Day et al., 2003; Meola et al., 1999, 2003; Schoser et al., 2004c]. A higher rate of premature labor and preterm deliveries also has been reported [Rudnik-Schoneborn et al., 2006].

At present there is no clear evidence of a congenital form of DM2 [Day et al., 2003]. However, there is evidence of anticipation, with earlier onset of more prominent symptoms, in studies of parent-child pairs [Schneider et al., 2000]. When symptoms occur in childhood, they typically are transient and relate to grip myotonia in the hands and thighs. Proximal weakness, muscle pain, cataracts, and occasional cardiac dysrhythmias usually do not develop until mid- or late adult life [Ricker et al., 1995; Thornton et al., 1994].

Genetics

DM2 results from an unstable four-nucleotide repeat expansion, CCTG, in intron 1 of the zinc finger protein 9 gene on chromosome 3q21 [Bachinski et al., 2003; Liquori et al., 2001, 2003]. The cause of the unstable expansion is unknown. The size of the CCTG repeat appears to increase over time in the same individual, and, like DM1, it is a dynamic gene defect [Day et al., 2003]. The size of the CCTG repeat in normal leukocyte DNA is less than 75 repeats [Day et al., 2003; Liquori et al., 2001]. The size in DM2 ranges from 78 to over 11,000 repeats [Day et al., 2003; Liquori et al., 2001]. The gene mutation responsible for DM2 appears to have arisen from a northern European founder [Bachinski et al., 2003; Liquori et al., 2003].

Pathophysiology

The molecular mechanisms leading to the manifestations of DM2 are believed to be similar to that in DM1, and relate to a toxic effect of the abnormally expanded RNA that accumulates in the muscle nuclei (see previous section on Pathophysiology of DM1). There is no apparent relationship between the putative functions of the zinc finger protein 9 gene at 3q21 and the DM1 gene at 19q13.3 or their gene products [Liquori et al., 2001]. Flanking genes are not similar for the DM2 and DM1 loci. A toxic effect of the ribonucleic acid made from the unstable, abnormally expanded, nucleotide repeats in the DM2 and DM1 genes is likely to serve as the common mechanism for their disease manifestations.

The cause of the weakness in DM2 is unclear. Patients with DM2, in contrast to patients with classic DM1, usually have only mild muscle wasting. However, there is an uncommon, adult-onset variant of DM2, termed proximal myotonic dystrophy [Udd et al., 1997], which causes severe wasting of proximal arm and thigh muscles as the illness progresses. Patients with the proximal myotonic dystrophy variant of DM2 have the identical CCTG repeat expansion at 3q21 that occurs in patients with DM2 [Bachinski et al., 2003]. The reason for the severe muscle wasting in this variant, compared with DM2 patients, is unknown. Whether individuals with proximal myotonic dystrophy [Udd et al., 1997] share an underlying mechanism responsible for muscle wasting that is similar to the mechanism in DM1 remains to be established. Two recent reports using cell models describe a reduction in the rate of protein translation in DM2 muscle cells, and propose that the accumulation of RNA containing long tracts of CCUG dysregulates translation and degradation of proteins in patients [Salisbury et al., 2009; Huichalaf et al., 2009]. More research is needed to confirm and extend these initial observations.

Clinical Laboratory Tests

Leukocyte DNA testing is available for DM2. DNA testing methodology used in the recent past to screen for DM2 may have failed to detect as many as 20 percent of affected individuals [Day et al., 2003]. Current methods use the more sensitive DNA testing methodologies for DM2 [Bachinski et al., 2003; Day et al., 2003].

Slit-lamp examination to detect early cataract formation and electromyography, especially of the first dorsal interosseous, anterior tibialis, and anterior thigh muscles, are useful. Grip myotonia varies in severity and may be absent. Some patients have an elevation (2- to 8-fold) in creatine kinase and gamma glutamyltransferase levels.

Patients with elevated creatine kinase values may have greater postoperative complications [Ricker et al., 1995]. A recent comparison of muscle biopsy findings in DM2 with those in classic DM1 indicates that there is less severe atrophy of fibers in DM2, and that in DM2 there are subgroups of very small type 2 fibers and nuclear clumps [Vihola et al., 2003]. Both DM2 and DM1 display abundant central nuclei on their biopsies [Day et al., 2003; Harper, 2001; Vihola et al., 2003], but it appears that DM2 is predisposed to type 2 fiber atrophy and DM1 to type 1 fiber atrophy [Cardani et al., 2009; Pisani et al., 2008; Bassez et al., 2008; Schoser et al., 2004a; Vihola et al., 2003].

Treatment

In general, the management of DM2 is similar to that of DM1, but there is less need for supportive care, such as bracing, scooters, or wheelchairs. Cataracts require monitoring, and serial monitoring with an electrocardiogram (EKG) is necessary to check for covert dysrhythmia. Disturbances in cardiac rhythm are less frequent in DM2, but abnormalities do occur [Wahbi et al., 2009; Schoser et al., 2004b; Day et al., 2003; Moxley et al., 2002]. Hypogonadism and insulin resistance need monitoring, as in DM1. Myotonia tends to be less marked and less troublesome in DM2 but, in specific circumstances, antimyotonia therapy is helpful, especially if muscle stiffness is frequent and persistent or if pain is prominent. Cognitive difficulties also occur in DM2, as in DM1, but become manifest in adult life and appear to be associated with decreased cerebral blood flow to frontal and anterior temporal lobes [Meola and Sansone, 2007; Meola et al., 1999] and decreased brain volume [Akiguchi et al., 1999; Chang et al., 1998]. The changes are less severe than in DM1. Their etiology is unknown but may relate to the toxic effect of intranuclear accumulations of abnormally expanded RNA. Management of these brain symptoms is similar to that for DM1.

A frequent and difficult problem in DM2 is the peculiar muscle pain described earlier [Auvinen et al., 2008; George et al., 2004]. The exact mechanism underlying the pain is unknown, and there is no well-established, effective treatment. Carbamazepine or mexiletine, along with nonsteroidal anti-inflammatory medications or acetaminophen ameliorates this pain in some patients.

Clinical Features

Generalized myotonia is the major clinical symptom in dominant and recessive forms of chloride channel myotonia congenita. Recent studies indicate that pain occurs in almost 30 percent of patients with chloride channel myotonia [Trip et al., 2009a], and as many as 75 percent have mild generalized muscle weakness that is slightly greater proximally [Trip et al., 2009a; Shalata et al., 2009; Bernard et al., 2008]. The pain has a close relation to fatigue and has a negative impact on the health status of those affected [Trip et al., 2009a]. Symptoms develop in the first or second decade of life. Myotonic stiffness occurs with sudden physical exertion after a period of rest. Repeated muscle contractions ameliorate the stiffness. This response is the “warm-up phenomenon,” which helps distinguish chloride channel myotonia congenita from certain forms of sodium channel myotonia that display increasing muscle stiffness with repeated contractions, a paramyotonic response. DM1 and DM2, like chloride channel myotonia, demonstrate the typical warm-up response.

In contrast to Thomsen’s disease, patients with autosomal-recessive myotonia congenita (Becker’s disease) have transient proximal muscle weakness. The transient weakness appears for a few seconds during the initial attempt at a specific movement after a period of inactivity [Zwarts and VanWeerden, 1989]. Muscle strength improves to normal after several strong contractions [Baumann et al., 1996; Zwarts and VanWeerden, 1989]. One study suggests that this transient weakness represents a transient depolarization block associated with prolonged recovery of muscle membrane excitability [McKay et al., 2006].

Patients have prominent muscle hypertrophy, especially in the legs, in both the autosomal-dominant and autosomal-recessive forms of myotonia congenita. Tendon reflexes, cerebellar function, sensation, and strength are normal. Myotonia can be noted on hand grip, after eye closure, and with lid lag. If patients lie supine for 5–10 minutes and suddenly arise, generalized myotonic stiffness in the proximal and paraspinous muscles becomes apparent.

Genetics

Point mutations in the gene for the skeletal muscle chloride channel cause both autosomal-dominant [Trip et al., 2008, 2009b; Fialho et al., 2007; Fahlke et al., 1997a; Koch et al., 1992] and autosomal-recessive [Trip et al., 2008, 2009b; Fialho et al., 2007; Koch et al., 1992] forms of myotonia congenita. Autosomal-dominant myotonia congenita (Thomsen’s disease) may vary considerably in age of onset and severity of myotonia [Duno et al., 2004; Koty et al., 1996]. Two recent reports describe marked myotonia, generalized moderate weakness, and generalized muscle hypertrophy in homozygous individuals in kindreds with dominant chloride channel myotonia [Bernard et al., 2008; Shalata et al., 2009]. These results demonstrate a dose effect with disease severity. It is now possible to screen for known point mutations in the chloride channel gene on chromosome 7 [Trip et al., 2008, 2009b; Fialho et al., 2007], and extensive genetic testing for more than 80 mutations is available in two laboratories, one in the United Kingdom and one in the Netherlands. The group in the Netherlands recommends a tandem analysis for gene mutations. They first perform DNA analysis of all 23 exons in the skeletal muscle chloride channel gene, and then proceed with DNA analysis of those individuals who test negative for chloride channel mutations, with probing of the exons in the skeletal muscle sodium channel gene known to cause sodium channel myotonia [Trip et al., 2008]. This approach has proven very informative in establishing a diagnosis.

Pathophysiology

Electrophysiologic studies in myotonic goats [Lipicky and Bryant, 1993] and human muscle tissue from patients with autosomal-dominant and autosomal-recessive [Koch et al., 1992; Rudel et al., 1994] myotonia congenita demonstrate a decreased chloride conductance. The decreased chloride conductance across the transverse tubular system renders the muscle membrane hyperexcitable, which leads to after-depolarization and repetitive firing, creating clinical myotonia. Both autosomal-dominant myotonia congenita (Thomsen’s disease) and generalized autosomal-recessive myotonia congenita (Becker’s disease) involve mutations at the same locus [George et al., 1993; Koch et al., 1992]. Current models for the chloride channel indicate that two subunits combine to form a double-barreled entry gate for chloride ions and a single outflow channel [Duffield et al., 2003; Fahlke et al., 1997a, 1997b; Saviane et al., 1999]. Dominant mutations affect the common outflow channel (slow-flow channel), and recessive mutations require involvement of the two faster-flow entry gates [Duffield et al., 2003]. The model proposes that involvement of only one entry gate does not cause clinical disease. Recessive mutations cause a pathologic reduction in chloride current because both fast gates undergo blockade, and dominant mutations cause pathologically reduced current because they affect the slower common exit channel for chloride ions. Recessive mutations are much more frequent than dominant mutations. Over 80 mutations are known to cause chloride channel myotonia [Colding-Jorgensen, 2005]. More than 50 percent of chloride channel mutations occur in exons 3, 8, and 11 [Fialho et al., 2007; Trip et al., 2008]. The variations in the clinical severity of certain very rare, dominantly inherited forms of chloride channel myotonia, such as “myotonia levior” [Ryan et al., 2002] and “fluctuating myotonia” [Wagner et al., 1998], are interesting, and point to limitations in our current version of the model as an explanation for the clinical spectrum of findings. A more recent report further emphasizes the limitation of the model. This report describes two unrelated families with the Becker recessive form and two unrelated families with the Thomsen dominant form of myotonia congenita, all of whom have a common R894X mutation [Duno et al., 2004]. The dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele. These findings suggest that allelic variation may be an important modifier of disease progression in myotonia congenita. One report of a family with Thomsen myotonia congenita describes a kindred with a T310M mutation and notes that family members with one mutated allele have mild manifestations, while the one family member who was homozygous for this mutation had severe stiffness, generalized muscle hypertrophy, and moderate weakness [Bernard et al., 2008]. Another more recent report also describes a gene dose effect, with worse disease severity (i.e., more severe myotonia and generalized weakness) in homozygous individuals who have a missense mutation of glycine to serine (G190S) in a well-conserved motif in helix D of the skeletal muscle chloride channel gene [Shalata et al., 2009].

The model for the chloride channel also does not provide an explanation for the transient weakness that is a prominent clinical feature in generalized autosomal-recessive (Becker’s myotonia) myotonia congenita. Its cause remains to be discovered. The model fails, as well, to provide an explanation for transient worsening that occurs occasionally during pregnancy. One potential clue comes from recent in vitro studies of testosterone and progesterone, which show rapid and reversible inhibition of both the normal and the mutated forms of skeletal muscle chloride channels expressed in Xenopus oocytes, caused by a prominent rightward shift in the voltage dependence of their open probability [Fialho et al., 2008]. Further study using more physiologic concentrations of these sex hormones in a more appropriate cell culture model, such as myoblasts or myotubes, is needed to establish the physiological significance of this effect.

Clinical Laboratory Tests

Evaluation of patients with suspected myotonia congenita should include consideration of other myotonic disorders, such as DM1, DM2, paramyotonia congenita, sodium channel myotonias of other types, and chondrodystrophic myotonia (Schwartz–Jampel syndrome). DM1 patients typically have facial and distal muscle weakness. DNA analysis reveals an abnormal expansion of [CTG]n repeats in the DMPK gene on chromosome 19. Patients with DM2 have an abnormal expansion of [CCTG]_n repeats in the zinc finger 9 protein gene on chromosome 3. Patients with chondrodystrophic myotonia (Schwartz–Jampel syndrome) have typical dysmorphic features, dwarfism, and distinctive myotonic discharges on electromyography, which are neurogenic in origin.

Distinguishing patients with chloride channel myotonia, either autosomal-dominant or autosomal-recessive forms, from those with sodium channel myotonic disorders is more difficult. Both cause myotonic stiffness and muscle hypertrophy, especially in the legs. One distinguishing feature of sodium channel myotonia is the paradoxical myotonia of the eyelids that develops with repeated forceful eye closure. Figure 96-3 shows the response to looking up and down and to eye closure in a patient with DM1. The patient in Figure 96-4 has sodium channel myotonia, exhibiting lid lag and persisting myotonia after forceful closure of the eyes. If this patient repeats the forceful closure of his eyes, his myotonia worsens. Persistent myotonia of the eyelids also occurred in this patient’s son. In contrast, patients with autosomal-dominant and autosomal-recessive forms of chloride channel myotonia exhibit warm-up after repeated contractions. One recent study comparing 32 patients with chloride channel myotonia to 30 patients with sodium channel myotonia observed the following differences between these two groups of patients [Trip et al., 2009b]. Compared to patients with sodium channel myotonia, patients with chloride channel myotonia have a higher frequency of: muscle weakness, 75 versus 37 percent; warm-up following repeated 3-second isotonic maximum grips, 100 versus 47 percent; and slowing in the time to arise from sitting to standing, 91 versus 67 percent. In contrast, compared to patients with chloride channel myotonia, patients with sodium channel myotonia had higher frequencies of: paradoxical myotonia, 50 versus 0 percent; and painful myotonia, 57 versus 28 percent [Trip et al., 2009b]. Patients with sodium channel myotonia also had earlier onset of symptoms: 4.4 years versus 10 years of age. Patients with chloride channel myotonia do not have a worsening of myotonic stiffness or paralysis after prolonged exposure of muscle to cold. To search for cold-induced paralysis, it is necessary to soak the hand or forearm muscles in cold water (15°C) for 15–20 minutes. If there is weakness with exercise after this cold exposure, this observation strongly favors sodium channel myotonia rather than chloride channel disease [Heatwole and Moxley, 2007; Carle et al., 2009; Webb and Cannon, 2008]. The subsequent section on sodium channel myotonia briefly describes the laboratory evaluation of the sodium channelopathy disorder, hyperkalemic periodic paralysis. Recent reports have provided protocols for complete screening of both the skeletal muscle chloride and sodium channel genes [Trip et al., 2008; Fialho et al., 2007]. The approach uses tandem analysis of the chloride channel gene, followed by analysis of the sodium channel gene, in individuals who already have had negative DNA analysis for DM1 and DM2, and have a negative history for periodic paralysis.

Fig. 96-3 Comparison of up and down gaze and eye closure in a woman with DM1 and a man with sodium channel myotonia associated with paramyotonia with eye closure.

Fig. 96-4 A patient with acetazolamide-responsive sodium channel myotonia.

The patient appears in Figure 96-1 with his father, who is also shown in Figure 96-3. Sequential photographs of the patient before and after forced closure of the eyes. Myotonia appears and worsens after repeated eye closure (e.g., paramyotonia).

Treatment

Antimyotonia treatment with mexiletine is often helpful [Heatwole and Moxley, 2007]. Before treatment with mexiletine is initiated, a baseline EKG is necessary to identify patients with unsuspected cardiac conduction abnormalities. Side effects of mexiletine, which are usually mild and dose-related, include dysgeusia, lightheadedness, and diarrhea. Tocainide, another lidocaine derivative similar to mexiletine, was another useful alternative [Kwiecinski et al., 1992], but it is no longer available. Isolated reports suggest that carbamazepine may be a readily available alternative antimyotonia medication for myotonia congenita [Berardinelli et al., 2000; Sheela, 2000]. Children with moderately severe myotonia develop heel-cord shortening and contractures at their elbows. If these contractures do not respond to stretching and other physical therapy exercises, it is appropriate to initiate antimyotonia treatment, even when patients do not complain of stiffness.

Clinical Features

Acetazolamide-responsive sodium channel myotonia often presents initially to the pediatrician rather than the neurologist with common complaints, such as clumsiness causing frequent falls, a lazy eye, growing pains, back muscle spasm, or stridor. Parents may observe that, after prolonged crying, an infant or young child will have “their eyes stuck.” This symptom is a manifestation of paradoxical eyelid myotonia that develops with repeated bouts of forceful closure of the eyes during crying. Myotonia is most apparent in the face, eyes, and larynx in very young patients. Stiffness in the hands, proximal limb muscles, and paraspinous muscles is more apparent in middle childhood. Muscle hypertrophy, especially in the legs, is frequent. Cerebellar function, sensory testing, tendon reflexes, and muscle strength are normal. Grip and percussion myotonia, as well as lid lag, are present. The severity of these complaints varies both in affected individuals within the same kindred and between kindreds. Episodes of painful muscle spasm occur in some patients, usually during or immediately after exercise. Pain is relatively infrequent in recessive and dominant chloride channel myotonias [Trip et al., 2009a – see section above on chloride channel myotonia]. In contrast, pain is common in acetazolamide-responsive sodium channel myotonia and DM2.

The clinical findings in myotonia fluctuans are similar to those described previously for acetazolamide-responsive sodium channel myotonia, with one important additional finding. The severity of the muscle stiffness fluctuates to a greater degree in this illness. On “good days,” the myotonia can vanish. The fluctuating myotonia also has an interesting relationship to prolonged exercise. A phenomenon termed exercise-induced delayed-onset myotonia occurs [Ricker et al., 1990]. Patients report that, after a period of rest following vigorous exercise, if they resume exercise “at the wrong time,” severe muscle stiffness may develop. The time interval between the period of rest and the resumption of exercise is critical. If it is only a few minutes or an hour or more, stiffness does not occur. During the intermediate time interval, the fluctuation and provocation of severe myotonia happen.

The myotonic symptoms in both acetazolamide-responsive sodium channel myotonia and myotonia fluctuans tend to persist throughout a patient’s lifetime. Some individuals note a lessening in severity in mid- to late adulthood. This finding may represent only an adjustment to the illness and a decrease in physical activity.

Genetics

Acetazolamide-responsive sodium channel myotonia results from a mutation in the gene for the skeletal muscle sodium channel [Ptacek et al., 1994b], as does myotonia fluctuans [Ricker et al., 1994b]. The mutations in these two disorders of the sodium channel are not identical. Separate mutations produce myotonia fluctuans [Ricker et al., 1994b]. Both disorders are autosomal-dominant.

Pathophysiology

Both of these nondystrophic sodium channel myotonic disorders worsen with an elevation in extracellular potassium. The myotonic stiffness can disable a patient totally under these circumstances. The specific mechanism by which the fluctuation in severity of myotonia occurs remains unclear, but it may relate in part to hormonal fluctuations. The levels of insulin, corticosteroids, and other hormones may exert an important influence on extracellular potassium levels [Ricker et al., 1994b].

Clinical Laboratory Tests

Routine DNA testing is not available; however, several research laboratories screen for known mutations in the gene for the sodium channel in selected patients [Trip et al., 2009b; Fialho et al., 2007; Fournier et al., 2006]. The remainder of the laboratory evaluation is as described previously for chloride channel myotonia.

Treatment

Acetazolamide often controls myotonic stiffness and pain in acetazolamide-responsive sodium channel myotonia [Heatwole and Moxley, 2007; Ptacek et al., 1994b]. This treatment usually ameliorates the muscle pain. Annual ultrasound of the abdomen is useful to detect early formation of kidney stones, which are a common complication of acetazolamide [Tawil et al., 1993]. Dysesthesia and dysgeusia may also occur with this medication. For attacks of severe muscle spasm and pain, cyclobenzaprine can be tried. Patients undergoing surgery require monitoring during and after the procedure for signs of worsening muscle stiffness. Maintaining plasma potassium levels between 3.8 and 4.2 mEq/L helps to decrease perioperative muscle stiffness. Stress, muscle tissue damage, and bleeding all elevate plasma potassium levels and worsen myotonia. Postoperatively, intravenous diazepam or lorazepam may be necessary to decrease myotonic stiffness, especially if patients are unable to take medications by mouth. Mexiletine is an effective alternative to acetazolamide and, if necessary, these drugs can be used in combination [Heatwole and Moxley, 2007].

The management of myotonia fluctuans is similar to that of acetazolamide-responsive sodium channel myotonia. Careful attention to the pattern and timing of exercise helps to decrease episodes of severe muscle stiffness. Intraoperative and postoperative monitoring is important, as noted previously.

Clinical Features

Table 96-4 outlines the major clinical and diagnostic features of hyperkalemic periodic paralysis, as well as important issues in management. All three forms are autosomal-dominant, with high penetrance in both sexes [Cannon, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Moxley, 2000]. Attacks begin in childhood and usually are brief, being shorter and more frequent than attacks in hypokalemic periodic paralysis. The attacks can occur with or without myotonia and, in certain families, hyperkalemic paralysis occurs in combination with coexisting paramyotonia congenita [Jurkat-Rott and Lehmann-Horn, 2007; Heatwole and Moxley, 2007; Finsterer, 2008; Cannon, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Moxley, 2000]. At the onset of an attack, myalgia may develop. Patients with hyperkalemic periodic paralysis plus myotonia frequently develop muscle stiffness and prominent paradoxical myotonia of the eyelids during attacks. Similar symptoms occur in patients with hyperkalemic periodic paralysis in association with paramyotonia congenita [Jurkat-Rott and Lehmann-Horn, 2007; Lehmann-Horn et al., 2004]. Most patients with hyperkalemic attacks manifest signs of myotonia and notice increasing muscle tension, especially in the paraspinous muscles.

Genetics

All clinical variants of hyperkalemic periodic paralysis result from mutations in the gene for the skeletal muscle sodium channel [Cannon, 2002; Lehmann-Horn and Jurkat-Rott, 1999; Miller et al., 2004; Ptacek et al., 1994b], but the exact mutation can differ, despite the fact that clinical symptoms are indistinguishable.

Pathophysiology

In hereditary primary hyperkalemic periodic paralyses with and without myotonia, the net movement of potassium is the opposite of that which occurs in hereditary hypokalemic periodic paralysis. There is an enhanced urinary excretion of potassium and sodium, a decrease in serum sodium concentration, and a decrease in or unaltered serum chloride level [Moxley, 1994]. These findings are consistent with the egress of potassium and entry of sodium into muscle cells during attacks. During attacks of weakness in both hyperkalemic periodic paralysis and in paramyotonia congenita, there is an abnormally increased sodium conductance, leading to depolarization of the muscle [Lehmann-Horn et al., 2004; Jurkat-Rott and Lehmann-Horn, 2007]. Patients with hyperkalemic periodic paralysis have a strong diurnal sensitivity to attacks of weakness, which occur primarily in the morning [Ricker et al., 1989]. This sensitivity may relate to circulating factors, such as glucocorticoids and beta-adrenergic hormones. Interestingly, salbutamol and metaproterenol, both beta-adrenergic drugs, are capable of increasing muscle strength during attacks [Lehmann-Horn et al., 2004; Heatwole and Moxley, 2007; Ricker et al., 1989].

Clinical Laboratory Tests

The primary laboratory evaluation involves monitoring of serum electrolytes during attacks to identify hyperkalemia or hypokalemia, and monitoring the EKG to search for any evidence of dysrhythmia or other conduction disturbance, such as the EKG changes that occur in Andersen–Tawil syndrome. A dominant family history helps to limit additional laboratory testing to a search for secondary forms of hyperkalemia, which might lead to muscle weakness. Laboratory evaluation for secondary hyperkalemic weakness should include a search for hormonal disturbances, such as insulin deficiency or adrenal insufficiency, or toxic effects of medications, such as beta-adrenergic antagonists, alpha-adrenergic agonists, digitalis intoxication, or the use of succinylcholine. Recently, a few research laboratories have established protocols for full gene screening for mutations in the skeletal muscle sodium, chloride, calcium, and potassium channel genes to search for a mutation to account for one of the forms of nondystrophic myotonia or one of the forms of periodic paralysis [Trip et al., 2009b; Fialho et al., 2007]. Genetic screening with DNA analysis needs to be pursued prior to performing provocative testing, since this testing requires hospitalization and monitoring by clinicians experienced in the management of attacks of periodic paralysis and their complications. In patients not observed during a spontaneous attack of weakness or posing a continuing problem in definite classification of the form of periodic paralysis, it may be necessary to perform provocative testing with oral potassium loading or exercise followed by potassium challenge [Moxley, 2000].

Treatment

Attacks of weakness in hyperkalemic periodic paralysis are seldom severe enough to require emergency room evaluation. Oral glucose hastens recovery. Severe attacks usually respond to 2 g/kg of glucose by mouth and 15–20 units of crystalline insulin subcutaneously. Occasionally, severe attacks may fail to respond to these treatments. Calcium gluconate, 0.5–2 g intravenously, is sometimes effective. Inhalation of beta-adrenergic agents, such as metaproterenol, every 15 minutes for three doses has also been utilized.

Preventive treatment includes avoidance of fasting, exposure to cold, and over-exertion. A prudent consumption of frequent meals high in carbohydrate content is helpful. Diuretics that promote kaluresis, such as hydrochlorothiazide and carbonic anhydrase inhibitors, are good primary therapies [Moxley, 2000; Jurkat-Rott and Lehmann-Horn, 2007; Heatwole and Moxley, 2007; Sansone et al., 2008; Sansone and Tawil, 2007].

Clinical Features

Symptoms develop usually during the first decade of life and have a predilection for facial, lingual, neck, and hand muscles (see Table 96-4) [Lehmann-Horn et al., 2004; Lehmann-Horn and Jurkat-Rott, 1999; Moxley, 2000; Heatwole and Moxley, 2007]. Attacks of increased muscle stiffness followed by paralysis occur on exposure to cold followed by exercise. The hallmark clinical sign is paradoxical myotonia or paramyotonia: that is, stiffness that worsens with repeated muscle contraction. This sign is most prominent in the muscles of eye closure. Clinical myotonia may be restricted to the eye muscles and not be apparent in grip or after percussion. Recent reports describe severe variants with onset in infancy for some affected individuals with occasional deaths due to respiratory causes [Kubota et al., 2009; Gay et al., 2008]. These recent reports point out certain mutations in the sodium channel gene that cause earlier onset of enhanced sensitivity to cold-induced worsening of myotonia and weakness that contributes to a more severe phenotype [Carle et al., 2009; Kubota et al., 2009; Gay et al., 2008; Fournier et al., 2006]. Other mutations that cause cold exposure and exercise-sensitive myotonia have led to the onset of progressive proximal muscle weakness resembling DM2 later in life [Schoser et al., 2007]. These variants emphasize the need for caution in predicting the prognosis for disease severity and long-term course, until we have a more complete understanding of the genotype and phenotype in paramyotonia congenita.

Genetics

Mutations in the gene for the skeletal muscle sodium channel in several locations cause paramyotonia congenita [Matthews et al., 2010; Webb and Cannon, 2008; Carle et al., 2009; Kubota et al., 2009; Gay et al., 2008; Fournier et al., 2006; Cannon, 2002; Lehmann-Horn et al., 2004; Lehmann-Horn and Jurkat-Rott, 1999; Miller et al., 2004], but they tend to fall into the following two general groups:

Certain mutations cause characteristic patterns on short exercise testing before and after muscle cooling [Fournier et al., 2006]. The more severe, early-onset patients with paramyotonia mentioned above have mutations in the cytoplasmic loop between domains 3 and 4 [Gay et al., 2008], at the calcium-chelation loop of the EF-hand helix-loop motif of the C-terminus [Kubota et al., 2009], and a Q270K mutation on the outermost part of the S5 segment of domain I [Carle et al., 2009]. Patients with paramyotonia congenita associated with hyperkalemic periodic paralysis have mutations in the cytoplasmic loop between domains 3 and 4 [Jurkatt-Rott and Lehmann-Horn, 2007; Bouhours et al., 2004; Lehmann-Horn et al., 2004; Lehmann-Horn and Jurkat-Rott, 1999]. There is considerable variation in the severity of symptoms both within and between kindreds, and this variation does not correlate closely with the exact mutation [Jurkatt-Rott and Lehmann-Horn, 2007; Lehmann-Horn and Jurkat-Rott, 1999]. One recent report indicates that the combined form of hyperkalemic periodic paralysis and paramyotonia congenita, with the severe phenotype beginning in infancy, involves a specific mutation: a methionine substitution at codon 704 (T704M) [Brancati et al., 2003]. More studies are necessary to establish this phenotype–genotype correlation [Jurkatt-Rott and Lehmann-Horn, 2007; Matthews et al., 2010].

Clinical Laboratory Tests

Standardized testing, using immersion of the hand and forearm in cold water for 15 minutes followed by exercise, is effective in provoking paramyotonic stiffness and paralysis in most patients [Moxley, 2000; Ricker et al., 1990]. Most cooperative children can tolerate this testing. If no clear evidence of cold-induced muscle stiffness and weakness is apparent, further laboratory testing, as indicated previously under hyperkalemic periodic paralysis and as noted under laboratory tests for chloride channel myotonia, may be necessary. Repetitive nerve stimulation of the ulnar nerve at the wrist as a short exercise test before and after cold exposure helps to identify certain forms of sodium channel myotonia, including paramyotonia congenita, but it is uncomfortable and has been standardized only in adults [Fournier et al., 2006]. DNA analysis to search for known mutations in the gene for the sodium channel is available in selected research laboratories, and may become routinely available in the future [Matthews et al., 2010; Trip et al., 2009b; Jurkatt-Rott and Lehmann-Horn, 2007].

Pathophysiology

As in hyperkalemic periodic paralysis caused by sodium channel dysfunction, paramyotonia congenita also has increased sodium conductance and excessive depolarization of the muscle membrane [Webb and Cannon, 2008; Cannon, 2002; Bouhours et al., 2004; Lehmann-Horn and Jurkat-Rott, 1999]. The electrophysiologic defect in hyperkalemic periodic paralysis differs from that in paramyotonia congenita. This difference is apparent in the response of forearm muscle to cooling and exercise. In hyperkalemic periodic paralysis, cooling of forearm muscle, followed by forceful contractions, leads to mild weakness, but muscle fibers do not display the marked depolarization observed in the muscle of patients with paramyotonia congenita. Treatment with tocainide, which is effective in paramyotonia congenita, does not reduce the mild weakness provoked by cooling and exercise in hyperkalemic periodic paralysis, in contrast to its beneficial protective effect on forearm muscle strength in paramyotonia congenita [Rudel et al., 1994]. In paramyotonia congenita, exercise after exposure to cold provokes muscle stiffness and, occasionally, prolonged paralysis. Recent in vitro studies of a highly thermosensitive mutation causing paramyotonia congenita showed destabilization of mutant channel slow inactivation in combination with defective fast inactivation, which may predispose to prolonged membrane depolarization, in turn leading to membrane inexcitability and paralysis [Carle et al., 2009]. More research is necessary to clarify the mechanism of cold-induced weakness in paramyotonia and its variation within individuals in the same and different kindreds.

Treatment

Mexiletine usually is effective in preventing attacks of cold-induced weakness [Heatwole and Moxley, 2007; Moxley, 2000]. In vitro studies indicate that mexiletine, a class 1b antiarrhythmic [Wang et al., 2004], and flecanide, a class 1c antiarrhythmic [Desaphy et al., 2004], both act by producing an open channel block of persistent late sodium currents. Tocainide, another class 1b antiarrhythmic, is also effective, but is no longer available. Patients with the combination of paramyotonia congenita plus hyperkalemic periodic paralysis require additional treatment with either a thiazide diuretic or acetazolamide.

Clinical Features

Attacks of hypokalemic periodic paralysis usually have their onset in the first or second decade, and about 60 percent of patients are affected before the age of 16 years [Matthews et al., 2009; Kim et al., 2007; Venance et al., 2006; Chabrier et al., 2008; Moxley, 1994]. Rarely, attacks occur in infancy [Chabrier et al., 2008]. Initially, attacks tend to be infrequent but eventually may recur daily. Diurnal fluctuations in strength may develop, so that patients demonstrate greatest weakness during the night or early morning hours and gradually gain strength as the day passes. During major attacks, the serum potassium level decreases but not always to below normal. There is urinary retention of sodium, potassium, chloride, and water [Moxley, 1994]. Oliguria or anuria develops during such attacks, and patients tend to be constipated. Sinus bradycardia and EKG signs of hypokalemia appear when the serum potassium falls below normal. Usually during the fourth and fifth decades of life, attacks become less frequent and may cease. However, repeated attacks may leave the patient with permanent residual weakness [Dalakas and Engel, 1983; Fontaine et al., 2007; Venance et al., 2006; Jurkatt-Rott et al., 2009]. A recent report highlights specific phenotypic differences for hypokalemic periodic paralysis caused by mutations in the calcium channel, compared to those caused by mutations in the sodium channel [Fontaine et al., 2007]. There is an earlier onset of disease in the calcium channel mutations, while myalgias are more common in the sodium channel mutations. On muscle biopsy, there is predominance of tubular aggregates in patients with the sodium channel mutations, and vacuoles in those with calcium channel mutations. Treatment with acetazolamide aggravates hypokalemic periodic paralysis caused by sodium channel mutations [Fontaine et al., 2007].

Genetics

In most kindreds, familial hypokalemic periodic paralysis results from missense mutations at charged residues of the S4 voltage-sensing segments in either the L-type voltage-gated calcium channel, Cav1.1, or in the voltage-gated sodium channel, Nav1.4 [Struyk and Cannon, 2007, 2008; Matthews et al., 2009; Jurkat-Rott et al., 1994, 2000; Ptacek et al., 1994a; Sternberg et al., 2001]. The mutations affect segment S4 of domains 3 and 4. The prevalence of familial hypokalemic periodic paralysis is approximately 1 in 100,000. The symptoms are more severe in males, as is the case in hyperkalemic periodic paralysis.

Pathophysiology

In hereditary hypokalemic periodic paralysis, the muscle fiber develops reduced excitability and an increased sodium conductance that, unlike sodium channel forms of periodic paralysis, cannot be prevented by application of the sodium channel blocker tetrodotoxin [Moxley, 1994]. The in vitro electrophysiologic behavior of muscle fibers with sodium channel mutations associated with hypokalemic periodic paralysis appears to be similar to those with mutated calcium channels [Cannon, 2002]. The precise mechanism by which the skeletal muscle calcium channel permits this inexcitability of the muscle fiber remains unknown. One recent theory suggests that the pathological effect of mutations in both the calcium and sodium channels that cause hypokalemic periodic paralysis results from voltage sensor dysfunction and impaired gating of these channels. However, this theory does not account for the sarcolemmal depolarization or the hypokalemia that are characteristic of hypokalemic periodic paralysis. An alternative hypothesis is that the mutations of both the sodium and the calcium channels affect a common gating pore current that becomes leaky [Struyk and Cannon, 2007, 2008]. The leak sensitizes myofibers to reduced serum potassium levels, and results in membrane depolarization [Jurkatt-Rott et al., 2009]. The reduced serum potassium level leads to a new resting potential at −60 mV, and the cationic leak increases action potential generation from this level, resulting in weakness and paralysis. More research is needed to clarify and confirm this alternative hypothesis.

Clinical Laboratory Tests

Evaluation of serum electrolytes and EKG during attacks of weakness is essential to diagnosis and treatment. Muscle biopsy is usually not necessary but may reveal vacuoles, especially in patients with fixed weakness [Fontaine et al., 2007]. In patients not observed during attacks of weakness, it may be necessary to undertake careful provocative testing if DNA analysis does not identify the responsible mutation [Matthews et al., 2009]. This testing requires hospitalization and continuous monitoring of the EKG, as indicated in previously published protocols [Moxley, 1994, 2000]. Occasionally, hypokalemic paralysis develops from acquired, secondary causes. Causes of secondary hypokalemic weakness include hypokalemia in association with hyperthyroidism, beta-adrenergic stimulation, excessive insulin, alkalemia, barium poisoning, poor potassium intake (e.g., alcoholics, anorexia nervosa), excessive potassium excretion (e.g., diarrhea, laxative abuse, profuse sweating during athletic training), and renal loss of potassium (e.g., renal tubular acidosis, osmotic diuresis, and medication use, such as large doses of penicillin antibiotics) [Moxley, 1994].

Treatment

Acute attacks may respond to oral potassium chloride (0.2–0.4 mmol/kg), repeated at 15- to 30-minute intervals [Moxley, 1994]. Monitoring EKG and serum potassium levels and muscle strength helps determine the frequency of these doses. Milder attacks resolve spontaneously, and mild exercise of the weakened muscles speeds recovery. If a patient has a severe attack and is unable to swallow or is vomiting, very cautious intravenous infusion of potassium may be necessary. Treating physicians should keep in mind the fact that a patient’s serum potassium levels do not represent a total body deficit of potassium, but rather a temporary intracellular shift. Therefore, potassium replacement formulas tend to overestimate the replacement needs and result in potentially dangerous hyperkalemia. Preventive therapy for attacks of hypokalemic weakness is usually needed. A low-sodium (2–3 g/day) and low-carbohydrate (60–80 g/day) diet, avoidance of exposure to cold and overexertion, and supplemental doses of potassium chloride taken 2–4 times daily are preventive measures that may help [Moxley, 1994]. However, no convincing data are available to indicate that oral potassium chloride prevents attacks.

Acetazolamide in divided doses usually abolishes attacks of weakness in most patients when taken daily [Moxley, 1994; Sansone et al., 2008]. Dichlorphenamide is another carbonic anhydrase inhibitor that is useful as preventive treatment, if acetazolamide proves ineffective [Dalakas and Engel, 1983; Moxley, 1994; Tawil et al., 2000; Sansone et al., 2008]. Both of these carbonic anhydrase inhibitors produce a metabolic acidosis, and despite their kaluretic action and their tendency to lower serum potassium levels, they appear to act on skeletal muscle to stabilize potassium flux, especially during insulin stimulation [Corbett et al., 1984]. Side effects are as described in the section on acetazolamide-responsive sodium channel myotonia and myotonia fluctuans. There are rare familial cases of hypokalemic periodic paralysis in which acetazolamide exacerbates attacks of weakness [Torres et al., 1981]. This weakness appears to be a consistent but not universal feature of hypokalemic periodic paralysis families carrying sodium channel mutations [Cannon, 2002; Venance et al., 2004]. In these families, triamterene or spironolactone may control the attacks.

Clinical Features

Andersen syndrome [Sansone and Tawil, 2007; Bendahhou et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002] or, as recently recognized, Andersen–Tawil syndrome [Bendahhou et al., 2003], is a rare inherited disorder accounting for less than 10 percent of all periodic paralysis (1:500,000) [Sansone and Tawil, 2007]. It is characterized by periodic paralysis, long QT syndrome, ventricular dysrhythmias, and skeletal developmental abnormalities. The early reports of this disorder raised the possibility of hyperkalemia during attacks of weakness, but as more specific identification of kindreds with Andersen–Tawil syndrome has occurred, it is apparent that the disorder occurs with both hyper- and hypokalemia [Sansone and Tawil, 2007]. One form is a variant of hypokalemic periodic paralysis [Bendahhou et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002]. Patients with this type of hypokalemic weakness have dysmorphic features, such as short stature, clinodactyly, and microcephaly, as well as ventricular dysrhythmias (Figure 96-5). Attacks of weakness develop during the first or second decade [Andersen et al., 1971; Sansone et al., 1997; Tawil et al., 1994]. The attacks of limb weakness can vary from mild, resembling those in the sodium channel form of hyperkalemic periodic paralysis, to severe, resembling the typical calcium channel form of hypokalemic periodic paralysis. The major difference is that, occasionally, the episodes of weakness are associated with syncopal attacks and, rarely, sudden death. The cardiac arrhythmias and extrasystoles improve with an elevation in extracellular potassium, while hypokalemia tends to aggravate the cardiac dysrhythmias. The majority of patients with Andersen–Tawil syndrome have point mutations in the KCNJ2 gene. About 15 percent have hyperkalemic episodes, 20 percent have normokalemic attacks, and the remainder have hypokalemic episodes [Sansone and Tawil, 2007]. In carriers of the potassium channel mutation, Kir2.1, associated with Andersen–Tawil syndrome, 64 percent had attacks of weakness, 71 percent had long QT intervals, and 78 percent had dysmorphic features [Tristani-Firouzi et al., 2002]. Cardiac symptoms can be provoked by digitalis; are refractory to disopyramide phosphate, propranolol, and phenytoin; and may respond to imipramine [Sansone et al., 1997; Tawil et al., 1994]. Weakness and cardiac symptoms in some patients occur following corticosteroid treatment [Bendahhou et al., 2007]. Patients with Andersen–Tawil syndrome have a neurocognitive phenotype that includes deficits in executive function and abstract reasoning, relative to their siblings [Yoon et al., 2006].

Fig. 96-5 Andersen’s syndrome (hyperkalemic periodic paralysis with cardiac dysrhythmias).

A, Facial appearance of a teenager with Andersen’s syndrome (hyperkalemic periodic paralysis with cardiac dysrhythmias). B, The hands of his mother, who also has mild dysmorphic features of Andersen’s syndrome. C, The electrocardiograph (EKG) in this teenage patient, demonstrating the typical dysrhythmia. During attacks of generalized weakness in which the serum potassium level rises above 5 mEq/L, the EKG in this patient typically returns to normal.

(From Sansone V et al., 1997; and Tawil R et al., 1994. Copyright 1994 Wiley-Liss, Inc., a Wiley Company. Reproduced with permission of John Wiley & Sons, Inc.)

Genetics

One of the responsible mutations involves the gene encoding the inward-rectifying potassium channel Kir2.1 [Ai et al., 2002; Andelfinger et al., 2002; Plaster et al., 2001; Sacconi et al., 2009]. Autosomal-dominant inheritance occurs with variable severity within families [Sansone and Tawil, 2007; Bendahhou et al., 2003; Miller et al., 2004; Tristani-Firouzi et al., 2002]. The mutation with the most potent dominant effect is the T75R missense mutation [Sansone and Tawil, 2007]. Aside from the individuals with known mutations in the Kir2.1 gene (over 30 identified), approximately 40 percent of cases with the clinical features of Andersen–Tawil syndrome have unknown mutations.

Pathophysiology

Kir2.1 channels are voltage-gated potassium channels called inward rectifiers. These comprise a family of voltage-related but not voltage-dependent channels, whose function is to stabilize the membrane potential and determine the shape of the terminal portion of the action potential [Sansone and Tawil, 2007]. KCNJ2 encodes the inward rectifier Kir2.1, a member of the Kir2x subfamily, which is the critical alpha subunit of cardiac Ik1, the inward rectifier current [Sansone and Tawil, 2007]. The channel is a dimer of subunits, each with two transmembrane-spanning domains called M1 and M2. The NH2 terminal is on the M1 segment and the COOH terminal is on the M2 segment. More than 30 point mutations have been described so far, and they are mostly localized on the intracellular COOH terminal [Sansone and Tawil, 2007].

The different mutations thus far identified appear to affect channel function through heterogeneous mechanisms [Sacconi et al., 2009; Sansone and Tawil, 2007]. These include:

Other gene mutations that cause Andersen–Tawil syndrome act by a mechanism of haploinsufficiency, probably affecting trafficking and assembly of second messengers via the interaction of abnormal amino-acid positioning along the muscle membrane where the channels are localized [Sansone and Tawil, 2007].

Clinical Laboratory Tests

Periodic monitoring of the EKG is important to identify covert dysrhythmias. DNA testing, as it becomes available, is helpful in establishing the diagnosis [Sansone and Tawil, 2007]. Secondary forms of periodic paralysis most be ruled out with assessments of thyroid, renal, and adrenal functions. Muscle biopsy may help to distinguish patients with Andersen–Tawil syndrome from those with other myopathic disorders, especially various congenital myopathies. Electrophysiologic cold studies are helpful in confirming the presence of skeletal muscle membrane and excitability using the exercise nerve conduction study, which, in many patients, can distinguish those with known sodium, chloride, and calcium channel mutations from individuals with Andersen–Tawil syndrome [Sansone and Tawil, 2007; Fournier et al., 2006].

Treatment

Acetazolamide in doses used to treat sodium channel forms of hyperkalemic periodic paralysis is sometimes effective in preventing attacks of weakness. Dichlorphenamide may provide an effective alternative if acetazolamide fails [Tawil et al., 2000; Sansone et al., 2008]. Cardiac dysrhythmias are less frequent if serum potassium is permitted to range from 4 to 4.4 mEq/L. However, this elevation in potassium may be difficult to achieve because it typically is not feasible with the use of carbonic anhydrase inhibitors. Occasionally, patients require the use of a spironolactone diuretic in combination with a carbonic anhydrase inhibitor to achieve a slightly higher serum potassium. Management of the cardiac dysrhythmia is best handled by a cardiologist. It is typically difficult to control.

Clinical Features

Attacks of thyrotoxic periodic paralysis are unusual in the first decade or early in the second decade of life, but tend to develop in the late teens and during the 20s. It is much more frequent in Asians and males; 95 percent of cases are sporadic [Ko et al., 1996; Moxley, 1994; Ober, 1992]. Precipitating factors include sleep, hot weather, and excessive physical activity [Hsieh et al., 2008]. Recurrent attacks of weakness may occur in over 60 percent of patients who have not returned to the euthyroid state [Hsieh et al., 2008]. Cardiac problems, including sinus tachycardia, atrial fibrillation, supraventricular tachycardia, and ventricular fibrillation, can occur [Hsu et al., 2003; Moxley, 1994; Ober, 1992].

Pathophysiology

Pathophysiology of thyrotoxic periodic paralysis remains a mystery, but it is clear that the hyperthyroid state is an essential factor in mediating the hypokalemia and attacks of weakness [Arimura et al., 2007; Moxley, 1994]. Patients have attacks only when they are hyperthyroid, and attacks cannot be precipitated by insulin and carbohydrate administration once patients become euthyroid, in contrast with patients with hereditary hypokalemic periodic paralysis [Moxley, 1994; Ober, 1992]. Even after patients have become euthyroid and symptom-free, paralytic attacks recur if the patient experiences a relapse into a thyrotoxic state or if hyperthyroidism is produced again with exogenous thyroid hormone [Arimura et al., 2007; Moxley, 1994; Ober, 1992]. Hyperthyroidism alters plasma membrane permeability to sodium and potassium, and increases responsiveness to catecholamines, probably through an increase in the sodium potassium adenosine triphosphatase in skeletal muscle [Ewart and Klip, 1995]. However, hypokalemia does not appear to be the primary regulator of weakness in thyrotoxic periodic paralysis because some patients regain their strength in the presence of persistent hypokalemia [Shayne and Hart, 1994]. Moreover, a degree of hypokalemia sufficient to provoke a paralytic attack in a hyperthyroid patient may have no effect when that same patient is euthyroid [Ober, 1992], emphasizing that the relationship between hypokalemia and thyrotoxic periodic paralysis is complex. The fact that propranolol can prevent paralytic attacks at a level of hypokalemia, which, in the same individual, typically precipitates weakness [Shiang et al., 2009; Ober, 1992], raises additional questions about the specific role of changes in serum potassium in the etiology of thyrotoxic periodic paralysis.

Genetics

The gene defect responsible for thyrotoxic hypokalemic periodic paralysis remains unclear. One report described an R83H mutation in the potassium channel gene, KCNE3 [Dias da Silva et al., 2002], in a man who developed symptoms with the onset of Graves’ disease. The mutation was found in 2 of 3 descendants. Three more recent reports have failed to confirm this observation. One study of 97 Chinese men with thyrotoxic periodic paralysis compared the genetic findings in this group to those in 77 Graves’ disease patients without periodic paralysis, and to 100 normal males [Kung et al., 2004]. None of the men with known thyrotoxic periodic paralysis had mutations in the calcium channel, sodium channel, or potassium channel genes previously reported to be associated with periodic paralysis. Another study describes an analysis of the entire coding sequence of the KCNE3 gene in 79 Chinese patients with thyrotoxic periodic paralysis and compares the findings with those from 111 men with thyrotoxicosis without periodic paralysis [Tang et al., 2004]. No mutations were found in the KCNE3 gene. A third report describes genetic studies in 19 Chinese men with thyrotoxic periodic paralysis and compares them to evaluations in 48 thyrotoxic patients and 32 normal individuals [Ng et al., 2004]. Recent studies of membrane excitability after exercise continue to support the hypothesis that paralytic attacks in thyrotoxic patients are due primarily to a pre-existing latent abnormal excitability of the muscle membrane, possibly genetic in origin [Arimura et al., 2007]. However, no mutations have been found in the calcium or sodium channel genes previously reported to cause hypokalemic periodic paralysis.

Clinical Laboratory Tests

Measurement of thyroid function tests and the EKG are essential in establishing the diagnosis and in directing treatment. Other aspects of clinical laboratory evaluation are as described for familial hypokalemic periodic paralysis.

Treatment

Treatment consists of antithyroid therapy until the patient achieves the euthyroid state. Preventive measures should be undertaken after treatment of the acute attack, as described for primary familial hypokalemic periodic paralysis. Propranolol is often effective in preventing attacks in thyrotoxic periodic paralysis [Ober, 1992]. One recent report has emphasized the importance of propranolol as an initial treatment, and has suggested caution in the use of potassium replacement [Tassone et al., 2004]. A recent prospective study of 78 patients given intravenous potassium as the sole treatment for an acute attack in thyrotoxic periodic paralysis noted that approximately 75 percent of patients required relatively moderate doses of intravenous potassium chloride, that being a total of 63 ± 32 mmol infused at a rate of 10 mmoles/hour to restore muscle strength [Shiang et al., 2009]. However, about 25 percent of these patients experienced paradoxical hypokalemia during the infusion of potassium chloride, and these patients had more marked elevation of free thyroid hormone, higher blood pressure, and higher heart rate on presentation [Shiang et al., 2009]. It appears that paradoxical hypokalemia during the administration of intravenous potassium chloride indicates more severe hyperthyroidism and hyperadrenergic activity, which may require blockage of intracellular potassium shift to prevent rebound hyperkalemia [Shiang et al., 2009]. The investigators indicated that beta-blocker therapy was especially desirable for treatment of these patients. Acetazolamide is ineffective and may worsen or precipitate symptoms in thyrotoxic hypokalemic periodic paralysis; it should be avoided [Moxley, 1994]. In general, beta-blocking drugs are helpful to use throughout the early stages of management until the patient becomes euthyroid.

Clinical Features

The phenotype of Schwartz–Jampel syndrome has considerable variability. Severe forms appear in infancy and milder forms usually develop manifestations between 2 and 3 years of age. Patients have a short neck, protuberant abdomen, and sparse subcutaneous tissue. Joint contractures develop, along with a typical facial appearance (small palpebral fissures, pursed lips, low hairline, and low-set ears). The abnormal facies becomes increasingly prominent with age. The bony abnormalities, such as pectus carinatum, kyphoscoliosis, pes planus, hip dysplasia, platybasia, and flattened small vertebrae often are apparent early in the disease. Patients have a stooped posture with their shoulders flexed forward. Muscle hypertrophy and hirsutism are common. Serum creatine kinase activity is mildly increased. In typical Schwartz–Jampel syndrome, range of motion at joints becomes progressively restricted, which may be due to unchecked myotonia. Although carpal tunnel syndrome is rare in childhood, it does occur with some frequency in Schwartz–Jampel syndrome [Van Meir and De Smet, 2003]. Malignant hyperpyrexia may occur, complicating orthopedic surgical procedures [Seay and Ziter, 1978]. Mental retardation is present in 25 percent of affected children, and developmental language disorder and attention-deficit disorder may be present [Paradis et al., 1997]. Severe microcephaly has been reported [Pinto-Escalante et al., 1997]. Orthopedic consultation may precede neurologic evaluation, and comments by a radiologist about the spinal x-ray appearance may point to the diagnosis of Schwartz–Jampel syndrome. On neurologic examination, the combination of action and percussion myotonia, hyporeflexia, typical facies and body appearance, and electromyographic evidence of continuous muscle fiber activity (high-frequency discharges both occurring at rest and exacerbated by muscle contraction) is diagnostic for Schwartz–Jampel syndrome.

Genetics

Genetic heterogeneity accompanies the phenotypic variability in Schwartz–Jampel syndrome. The Schwartz–Jampel syndrome is diagnosed in early childhood by the presence of myotonia, short stature, masklike facies, muscle pseudohypertrophy, skeletal dysplasia with bone and joint abnormalities, and growth retardation [Aberfeld et al., 1965; Cao et al., 1978; Schwartz and Jampel, 1962]. This classic form of Schwartz–Jampel syndrome, proposed as type 1A [Giedion et al., 1997], is autosomal-recessive and associated with 30 mutations, including truncated and missense mutations, in the HSPG2 gene that encodes perlecan. The responsible gene resides on chromosome 1p34–p35 [Rodgers et al., 2007; Echaniz-Laguna et al., 2009; Stum et al., 2006; Arikawa-Hirasawa et al., 2002]. Perlecan is a large heparin sulfate proteoglycan, present in all basement membranes. It participates in cell adhesion, growth factor signaling, and maintenance of the basement membrane [Iozzo, 2005]. The hypomorphic effects of these mutations result in a decrease in the amount of perlecan in basement membranes, but not in the complete absence of this protein [Echaniz-Laguna et al., 2009]. The defective protein that is encoded leads to abnormal cartilage development and anomalous neuromuscular activity [Rodgers et al., 2007; Echaniz-Laguna et al., 2009]. A similar Schwartz–Jampel syndrome, type 1B, is recognizable at birth with more pronounced bone dysplasia. A more severe form of the syndrome, designated type 2, manifests at birth with increased mortality and bone dysplasia. More severe skeletal abnormalities and feeding difficulties are present [Dagoneau et al., 2004; Al Gazali et al., 1996]. Death resulting from respiratory complications may occur in type 2 [Dagoneau et al., 2004]. This severe neonatal form, often referred to as SJS type 2, results from null mutations of the gene that encodes the leukemia inhibitory factor receptor (LIFR) [Dagoneau et al., 2004]. The LIFR is a receptor for a variety of neurotrophic cytokines, and a null mouse model showed a reduced number of astrocytes in the spinal cord and brainstem, suggesting that the muscle stiffness observed in SJS type 2 may be of central nervous system origin [Ware et al., 1995]. The presence in neonates of chondrodysplasia; congenital bowing of shortened femora and tibiae; and facial manifestations consisting of a small mouth, micrognathia, and pursed lips should suggest the diagnosis of Schwartz–Jampel syndrome [Spranger et al., 2000].

Pathophysiology

The electrophysiologic evidence noted earlier emphasizes that the hyperexcitability of nerve-muscle transmission in Schwartz–Jampel syndrome relates to alterations at the neuromuscular junction secondary to a deficiency of perlecan. Recent evidence indicates that perlecan is a key molecule for localizing acetylcholine esterase at the synapse of the neuromuscular junction [Echaniz-Laguna et al., 2009; Rodgers et al., 2007; Stum et al., 2008; Arikawa-Hirasawa et al., 2002]. Studies of muscle biopsies of Schwartz–Jampel syndrome patients demonstrate nonspecific alterations in muscle fibers on typical histochemical staining, and weak immunostaining of perlecan with domain-specific antiperlecan antibodies [Arikawa-Hirasawa et al., 2002]. It seems likely that a deficiency of perlecan at the neuromuscular junction in Schwartz–Jampel syndrome allows sufficient but altered regulation of neuromuscular transmission. This alteration, in turn, leads to continuous muscle fiber activity and myotonic-like muscle contractions. Absence of perlecan, in contrast, may not permit sufficient neuromuscular transmission and accounts for the rapid demise of the patient and the lack of clinical signs of myotonic-like muscle contractions. The electromyographic findings differ from classic myotonic discharges that disappear at rest, have a lower frequency, and wax and wane [Huttenlocher et al., 1969; Taylor et al., 1972]. Striking high-frequency potentials associated with clinical myotonia are demonstrated electrophysiologically. Discharges often occur in bursts of motor unit potentials firing at rates 150–300 Hz for a few seconds, and often start and stop abruptly. The amplitude of the response typically wanes, and discharges may occur spontaneously or be initiated by needle movement or voluntary contraction. These findings are more typical of neuromyotonia, not classical myotonia, in which potentials fire at rates of 20–80 Hz. Electrical silence does not occur during rest, during general anesthesia, or after curarization [Taylor et al., 1972]. Muscle biopsy may demonstrate myopathic findings [Huttenlocher et al., 1969]. Computed tomography of muscles reveals diffuse high attenuation in sternocleidomastoid muscles and low attenuation in the paraspinal, quadriceps, sartorius, soleus, and gastrocnemius muscles [Iwata et al., 2000]. Somatosensory-evoked potentials are delayed [Singh et al., 1997], although visual and brainstem auditory-evoked potentials and nerve conduction velocities are normal. Local infusion of curare abolishes continuous discharges in some patients [Edwards and Root, 1982; Taylor et al., 1972]. Recent studies in the mouse model of Schwartz–Jampel syndrome, caused from a missense mutation in the HSPG2 gene, demonstrate that a deficiency of perlecan provokes neuromyotonia that has its origin in distal portions of the axon, and that the neuromyotonia is abolished with local curare administration or axotomy [Echaniz-Laguna et al., 2009].

Treatment

Therapy in Schwartz–Jampel syndrome is supportive and focuses on specific symptoms and potential complications. Orthopedic consultation and physical and occupational therapy are necessary to treat the bony deformities and contractures. Carbamazepine (20 mg/kg/day) in infants [Squires and Prangley, 1996; Topaloglu et al., 1993] and extended release therapy in older children have been reported to control myotonia and continuous muscle fiber activity. Procainamide is another potential antimyotonia treatment [Huttenlocher et al., 1969] and phenytoin may provide a modest benefit [Edwards and Root, 1982; Taylor et al., 1972]. Response to other antimyotonia drugs, such as mexiletine, has not been reported. Some patients require nasal bilevel positive airway pressure for obstructive sleep apnea [Cook and Borkowski, 1997] and gain some benefit from levator aponeurosis surgery [Cruz et al., 1998]. Anesthesiology consultation before surgery is prudent, since difficulty with intubation [Cook and Borkowski, 1997] and malignant hyperthermia [Seay and Ziter, 1978] are potential complications. Early initiation of treatment tends to lessen skeletal malformations [Squires and Prangley, 1996]. Micrognathia and palate constriction hinder tooth alignment and lead to displacement, impaction, and crowding of teeth [Diaz-Serrano et al., 2006]. These conditions facilitate dental plaque accumulation and contribute to generalized gingivitis and the onset of multiple caries. Myotonia affects the masticatory muscles and leads to rigidity of temporomandibular joints and temporomandibular disorders [Diaz-Serrano et al., 2006]. Botulinum toxin A injections may have a synergistic interaction with carbamazepine therapy in selected patients and improve jaw opening and facial muscle control [Aburahma et al., 2009].

Clinical Features

There are six forms of familial episodic ataxia currently classified, all rare and autosomal-dominant; the most common is episodic ataxia type 2, caused by mutations in CACNA1A, a gene that encodes the alpha 1A subunit of the main transmembrane neuronal voltage-gated calcium channel [Strupp et al., 2007]. However, the form of episodic ataxia most likely to resemble a myotonic-like clinical appearance is episodic ataxia type 1. The classic description of episodic ataxia type 1 includes the appearance of sudden episodes of cerebellar ataxia, lasting a few minutes, often provoked by startle, and beginning in childhood [Tomlinson et al., 2009; Rajakulendran et al., 2007; Brunt and van Weerden, 1990]. Some patients display prominent myokymia [Van Dyke et al., 1975]. However, recent clinical studies demonstrate that there is considerable phenotypic variation in episodic ataxia type 1 [Eunson et al., 2000; Kinali et al., 2004; Klein et al., 2004]. Some patients have grip myotonia, muscle stiffness, limited jaw opening, contractures (elbows and ankles), muscle hypertrophy, and kyphoscoliosis [Kinali et al., 2004], a clinical picture that resembles the childhood form of Schwartz–Jampel syndrome. Some individuals within a kindred only display seizures and have no episodes of ataxia or muscle stiffness [Tomlinson et al., 2009; Rajakulendran et al., 2007; Eunson et al., 2000]. In contrast, one report describes a patient with prolonged episodes (10–12 hours in duration) of painful muscle stiffness, triggered by fever and exertion, and associated with wrist flexion, thumb adduction, and myokymia in the periorbital muscles [Klein et al., 2004]. Ataxia was not a feature of these episodes. Dysarthria and double vision, along with swelling of the feet, occurred at the onset of attacks in this patient [Klein et al., 2004]. Tendon reflexes may be diminished, normal, or hyperactive. Electromyographic studies reveal continuous myokymic discharges and occasional neuromyotonic discharges [Tomlinson et al., 2009; Gutmann and Gutmann, 2004]. Nerve conduction studies are normal. Usually, the clinical picture and the family history of a dominantly inherited episodic disorder confirm the diagnosis.

Genetics and Pathophysiology

Episodic ataxia type 1 is caused by mutations in the KCNA1 gene encoding the Kv1.1 potassium channel alpha subunit [Browne et al., 1994]. Over 20 heterozygous mutations of a single-exon KCNA1 gene on chromosome 12p13 have resulted in episodic ataxia type 1 [Tomlinson et al., 2009]. The majority are missense point mutations. Evidence suggests that the specific molecular defect and the phenotype vary with the location of the mutation [Tomlinson et al., 2009; Rajakulendran et al., 2007; Klein et al., 2004; Rea et al., 2002]. Mutations that cause typical episodic ataxia type 1 (T226A, T226M, T226R, T226K, V4041, I177N) or neuromyotonia (P244H) alone are associated with altered kinetics of the potassium channel [Rajakulendran et al., 2007; Rea et al., 2002]. A mutation (R417stop) that causes a severe medication-resistant form of episodic ataxia type 1 impairs both tetramerization of the R417stop with the wild type of hKv1.1 subunits and the membrane targeting of the heterotetramers [Eunson et al., 2000]. Two other mutations (T226R, A242P), which lead to a severe phenotype of episodic ataxia type 1, including seizures, produce a combination of defects in channel assembly, membrane trafficking, and abnormal channel kinetics [Rea et al., 2002]. Another mutation, which involves a single nucleotide change at position 785 T>C, causes prolonged (10–12 hours), painful episodes of stiffness triggered by fever and exertion. These clinical findings [Klein et al., 2004] are similar to those in patients with antibody-mediated acquired generalized peripheral nerve hyperexcitability [Hart et al., 2002], and have led the investigators to hypothesize that the 785 T>C mutation causes channel dysfunction similar to that in the autoimmune disorder [Klein et al., 2004]. Further research is necessary to establish phenotype–genotype relationships. Electromyographic studies are often helpful in distinguishing episodic ataxia type 1 from episodic ataxia type 2 by revealing the abnormal peripheral nerve excitability that is apparent from the neuromyotonic discharges observed [Tomlinson et al., 2009].

Treatment

Therapy is symptomatic. Reducing opportunities for stress, startle, and overexertion lessens the frequency of episodes. Physical therapy and orthopedic consultation are helpful in patients with contractures. Acetazolamide may reduce episodes of ataxia, but carbamazepine is necessary to control muscle stiffness and myokymia [Tomlinson et al., 2009; Klein et al., 2004]. Phenytoin can also ameliorate myokymia and stiffness [Kinali et al., 2004].

Clinical Features

Acquired generalized peripheral nerve hyperexcitability represents a heterogeneous group of disorders that have included diagnoses such as Isaacs’ syndrome, cramp-fasciculation syndrome, and neuromyotonia [Gutmann and Gutmann, 2004; Hart, 2000; Hart et al., 2002]. Autoimmune, toxic, degenerative, and hereditary forms are included in the classification [Hart et al., 2002]. The core clinical symptoms are muscle twitching, exercise-triggered muscle cramps, and muscle stiffness [Hart et al., 2002]. Delayed relaxation after muscle contraction (pseudomyotonia) occurs less commonly (36 percent) [Hart et al., 2002]. Acquired generalized peripheral nerve hyperexcitability is very uncommon in childhood [Gonzalez et al., 2008]. In a series of 42 patients, only 3 patients were younger than 20 years of age (5, 10, and 15 years of age) [Hart et al., 2002]. One of these patients developed symptoms in early childhood and went untreated for many years. He had growth retardation and presented for evaluation in a wheelchair with severe muscle stiffness and cramps that had been mistaken for spasticity. Patients typically have normoactive or diminished tendon reflexes, and approximately one-third have sensory complaints. Excessive sweating is common (50 percent), but specific alterations of the autonomic nervous system are not. At the time of presentation, most patients have muscle overactivity affecting the legs alone, or legs and trunk combined [Hart et al., 2002]. Distinction between neuromyotonia and other entities, such as cramp-fasciculation syndrome, stiff person syndrome, and rippling muscle disease (a form of caveolinopathy, an inherited myopathy) lies in the clinical and electromyographic evaluation, along with screening for antibodies for the voltage-gated potassium channel [Gonzalez et al., 2008]. Electromyography reveals spontaneous firing of motor units as doublet, triplet, or multiple discharges that have a high burst frequency (40–400 Hz), and in more than 90 percent of cases, the discharges occur at irregular intervals of 1–30 seconds [Hart, 2000]. Voluntary contractions or electrically evoked contractions often provoke prolonged after-discharges. Abnormal spontaneous activity can occur without visible myokymia. These discharges disappear after blockade of neuromuscular transmission, and lessen or disappear in some patients after epidural anesthesia or proximal nerve block [Hart, 2000]. These findings support the hypothesis that the spontaneous discharges result from peripheral nerve hyperactivity [Hart, 2000; Hart et al., 2002].

Pathophysiology

Immune-related diseases, such as myasthenia gravis, diabetes mellitus, and rheumatoid arthritis, are more frequent in acquired generalized peripheral nerve hyperexcitability, as is lung cancer. Approximately 40 percent of patients have antibodies to the voltage-gated potassium channel [Hart et al., 2002], and these antibodies appear to have a central role in the pathophysiology [Hart et al., 2002; Tomimitsu et al., 2004; Gonzalez et al., 2008]. Studies of cultured cell lines incubated with patient sera indicate that there is antibody-mediated suppression of outward-gated potassium current [Tomimitsu et al., 2004]. Recent in vitro investigations using neuronal cell lines indicate that the reduction in potassium currents by antibodies to the voltage-gated potassium channel is independent of added complement; however, F(ab′)2 fragments isolated from patient sera significantly reduce potassium currents. These findings make it likely that cross-linking of the voltage-gated potassium channels by divalent antibodies is an important mechanism in reducing the potassium current [Tomimitsu et al., 2004]. Most cases are caused by antibodies in the immunoglobulin G subclass, but some recent cases appear to be related to potassium channel antibodies only appearing in the immunoglobulin M-containing fraction [Kurono et al., 2006]. This raises the possibility of new treatment strategies directed at these patients in the future. Other circulating factors cause acquired generalized peripheral nerve hyperexcitability, such as timber rattlesnake envenomation [Gutmann and Gutmann, 2004]. The venom enters the circulation, causing generalized myokymia involving the face and extremities. Symptoms abate within hours of administering antivenin therapy [Gutmann and Gutmann, 2004].

Treatment

Carbamazepine and phenytoin are the primary symptomatic medications for the neuromyotonia and usually control symptoms of muscle overactivity [Hart, 2000]. Occasionally, effective control of the neuromyotonia alone is sufficient to produce resolution of symptoms [Gonzalez et al., 2008]. In refractory cases or in the initial management of severe cases, plasma exchange [Hart, 2000; Hayat et al., 2000] or immune globulin infusion [Hart, 2000] may produce rapid resolution of symptoms. Prednisone and azathioprine may prove useful for long-term treatment, as well as other immunosuppressive agents [Hart, 2000], but long-term controlled trials are necessary to confirm this clinical impression.

Clinical Features

Stiff person syndrome is a rare neurologic disorder with autoimmune features. Its primary manifestation is progressive, severe muscle rigidity or stiffness, most prominently affecting the spine and lower extremities [Dalakas et al., 2000; Murinson et al., 2004; Rakocevic et al., 2004; Murinson and Guarnaccia, 2008]. Occasionally, the muscle stiffness may resemble myotonia with a delay in relaxation, but the typical manifestations in skeletal muscle are distinguished readily from true myotonia. In stiff person syndrome, there is an insidious onset of muscular rigidity in limb and axial musculature [Dalakas et al., 2000]. The stiffness is most prominent in the abdominal and thoracolumbar muscles and causes difficulty in turning and bending. Electromyographic recordings demonstrate that there is continuous co-contraction of agonist and antagonist muscles, and the patient is unable to relax. Episodic muscle spasms that occasionally may resemble myotonic-like contractions are superimposed on this rigidity and are precipitated by unexpected noises, tactile stimuli, or emotional stress. These manifestations occur in the absence of any other neurologic disease or underlying chronic pain syndrome that might produce prolonged muscle rigidity and spasms. Many patients have an elevated titer of antibodies to glutamic acid decarboxylase antibodies, and they often have diabetes or other autoimmune diseases [Dalakas et al., 2000; Koerner et al., 2004; Murinson et al., 2004; Rakocevic et al., 2004]. Uncommonly, in perhaps 5 percent of stiff person syndrome patients, there is a paraneoplastic origin for the illness, associated with antibodies against amphiphysin [Petzold et al., 2004]. A recent study of 116 patients with stiff person syndrome related to glutamic acid decarboxylase antibodies compared their clinical findings to those of 11 patients with stiff person syndrome related to amphiphysin antibodies and found distinctively different patterns of muscle involvement in the two groups [Murinson and Guarnaccia, 2008]. For patients with high levels of glutamic acid decarboxylase antibodies, the pattern of greater muscle involvement was as follows: legs and spine > abdomen and arms > neck > bulbar. The patients with stiff person syndrome related to amphiphysin antibodies had a different pattern, frequently involving the arms and neck [Murinson and Guarnaccia, 2008]. Almost all the patients with stiff person syndrome related to glutamic acid decarboxylase antibodies had stiffness, rigidity, or increased tone, and the majority had pain [Murinson and Guarnaccia, 2008]. The age range for males was 14–82 years and for females 30–73 years.

Stiff person syndrome is rare in children [Murinson and Guarnaccia, 2008; Saiz et al., 2008; Murinson et al., 2004]. One recent study of 116 stiff person syndrome patients with elevated levels of glutamic acid decarboxylase antibodies included only 1 teenage patient; the remaining 115 patients were older than 30 years of age [Murinson et al., 2004]. In an earlier study of 20 selected patients, the average age was 41.2 years [Dalakas et al., 2000], and in another recent report of 16 patients with stiff person syndrome, the ages ranged from 37 to 62 years, with a median age of 52 years [Rakocevic et al., 2004].

Pathophysiology

Electromyographic investigations in patients with stiff person syndrome disclose the presence of low-frequency firing of normal motor units, especially in the muscles of the trunk, which increases for seconds or minutes to a dense pattern during a spontaneous or provoked muscle spasm [Koerner et al., 2004; Meinck et al., 1995]. These bursts of electrical activity are highly variable in location, duration, and intensity. Investigators have described a stereotyped motor response to stimulation of peripheral nerves in stiff person syndrome patients that consists of a sequence of 1–3 synchronous myoclonic bursts, 60–70 milliseconds after median nerve stimulation, followed by tonic decrescendo activity over a number of seconds [Meinck et al., 1995]. This response is called spasmodic reflex myoclonus, and explains certain aspects of the pathophysiology of stiff person syndrome. The stiffness appears to be a fragment of spasms, and both are due to a common neuronal mechanism of abnormal regulation of interneurons in the spinal gray matter [Meinck et al., 1995]. Other studies support this mechanism and suggest an important role for motor cortex hyperexcitability in stiff person syndrome [Koerner et al., 2004]. A study using transcranial magnetic stimulation methodology points out that the elevation of glutamic acid decarboxylase antibodies directly correlates with the enhanced cortical excitability and that gamma-aminobutyric acid-mimetic medications reduce intracortical facilitation [Koerner et al., 2004]. These observations suggest a clear role for glutamic acid decarboxylase antibodies in mediating the stiffness and muscle spasms. However, the precise pathophysiologic role of glutamic acid decarboxylase antibodies in stiff person syndrome requires further investigation [Saiz et al., 2008].

One recent study of 16 adults with stiff person syndrome notes that there is no correlation between the glutamic acid decarboxylase antibody titers in serum or cerebrospinal fluid and the severity of disease [Rakocevic et al., 2004]. The authors emphasize that an elevation of glutamic acid decarboxylase antibodies serve as an excellent marker for stiff person syndrome, but monitoring their titers during the course of the disease may not have practical value. Another recent study stresses the importance of establishing an appropriate threshold elevation of glutamic acid decarboxylase antibodies before making a diagnosis of stiff person syndrome [Murinson et al., 2004] because nonaffected individuals, such as some diabetic people, may have modest elevations of glutamic acid decarboxylase antibodies. This study also notes that elevation of glutamic acid decarboxylase antibodies do not correlate with the age or duration of stiff person syndrome [Murinson et al., 2004]. It is interesting to note that two children born to two different mothers with stiff person syndrome had high titers of glutamic acid decarboxylase antibodies for the first 24 months of life, and, having reached the ages of 6 and 8 years, they have not had any manifestations of stiff person syndrome [Nemni et al., 2004]. Clinical criteria remain the benchmark for the diagnosis of stiff person syndrome.

Treatment

Diazepam is an effective medication to control muscle spasms and the dose needs to be titrated to each patient [Murinson and Guarnaccia, 2008]. Its beneficial effect is likely mediated by its actions on the gamma-aminobutyric acid (GABA_A) receptor. Baclofen, gabapentin, clonazepam, dandrolene, and vigabatrin have provided lesser benefit. Plasma exchange and intravenous immune globulin infusions have proved effective, especially in times of acute worsening or in patients who develop refractoriness to symptomatic therapy with these medications [Donofrio et al., 2009; Dalakas et al., 2000, 2001]. Controlled trials are needed to establish the role of long-term treatment with immunosuppressive medications, such as corticosteroids and mycophenolate, and are also needed to determine the comparative effectiveness of plasmapheresis and immune globulin therapy.