eMedicine Specialties > Neurology > Neuromuscular Diseases

Schwartz-Jampel Syndrome

Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center
Eric Dinnerstein, MD, Consulting Staff Neurologist, Maine Neurology

Updated: Feb 2, 2007

Introduction

Background

Schwartz-Jampel syndrome (SJS) is a term now applied to 2 different autosomal recessive inherited conditions, sometimes termed SJS type I and SJS type II. Both are very rare. SJS type I has 2 recognized subtypes, IA and IB, which are similar except that type IB manifests earlier and with greater severity. The most commonly recognized and described type is IA, which exhibits muscle stiffness, mild (and largely nonprogressive) muscle weakness, and a number of minor morphological abnormalities. In affected patients, problems with motor development frequently become evident during the first year of life. Usually, the characteristic dysmorphic features lead to an early diagnosis, no later than age 3 years. Types IB and type II (now known to be a separate disease more commonly referred to as Stuve-Wiedemann syndrome) are discussed in further detail later.

The first described cases of SJS were reported in 1962 by Oscar Schwartz and Robert S. Jampel in the Archives of Ophthalmology in an article titled "Congenital blepharophimosis associated with a unique generalized myopathy." In this paper, the authors present the case of 2 siblings, a 6-year-old boy and a 3-and-a-half-year-old girl, who had the following clinical characteristics:

• Congenital blepharophimosis (ie, decreased palpebral fissure with normal eyelid development)
• Unusual facies characterized by a puckered facial appearance
• Small muscle mass and joint deformities (eg, coxa valga, irregularity of the capital femoral epiphyses, pectus carinatum ["pigeon breast"])
• Hypertrichosis of the eyelids
• Slightly elevated serum aldolase level

Electromyography (EMG) was not performed. The authors opined that the disease might represent a generalized problem with muscle and tendon development during infancy.

As mentioned above, certain subtypes of SJS are now recognized. Type IA is the classic type described by Schwartz and Jampel. Types IB and a type II have also been delineated. Type IA becomes apparent later in childhood and is less severe. Type IB is apparent immediately at birth and is more severe clinically, although typically compatible with life and even long-term survival. Types IA and IB derive from mutations of the same gene, the HSPG2 gene, which codes for perlecan, a heparin sulfate proteoglycan.

Type II, like type IB, is apparent immediately at birth. The patients look similar to those with type IB. However, it was known for many years that type II does not map to the same chromosome as types IA and IB. It is now known that type II relates to a mutation in a different gene, the gene for the leukemia inhibitory factor receptor (LIFR). This is the same disease as Stuve-Wiedemann syndrome, which has been known separately, mainly in the rheumatologic and orthopedic literature, rather than the neurologic literature.

The cardinal features of type II are joint contractures, bone dysplasia, and small stature. Infants with type II have severe respiratory difficulties and feeding problems. Hypotonia (rather than stiffness) is prominent. Frequent bouts of hyperthermia have been described (possibly related to mitochondrial dysfunction). A high infant mortality rate is associated with this condition. Long-term survivors are rare. However, 2 long-term survivors, ages 3 and 12 years, have recently been reported (Di Rocco, 2003). In addition to problems with bone dysplasia, these children also manifested dysautonomic and neuropathic features, including reduced patellar reflexes, lack of corneal reflexes, and paradoxical perspiration at low temperatures. Their tongues lacked fungiform papillae (in addition to showing ulcerations).

Considerable justification can be made for dropping the term SJS type II and simply referring to the condition as Stuve-Wiedemann syndrome. The disease is not technically that which Schwartz and Jampel described. Nevertheless, the term SJS type II is included in this discussion. Because so few patients with Stuve-Wiedemann syndrome have survived long term, most of the clinical information provided below pertains to SJS types IA and IB. Information pertinent to Stuve-Wiedemann syndrome will be identified as such. More genetic details of both diseases are provided in Causes.

Pathophysiology

The clinical features of muscle stiffness in SJS type I somewhat resemble those seen in myotonic disorders, stiff person syndrome, or Isaacs syndrome. The stiffness does not disappear with sleep or benzodiazepine treatment (as in stiff person syndrome), and it is not abolished reliably with curare (as in Isaacs syndrome).

Neurophysiologic examination typically shows continuous electrical activity (similar to myotonic discharges). However, the electrical activity often lacks the waxing and waning quality of true electrical myotonia and might be better described as complex, repetitive discharges. At other times, the pattern resembles neuromyotonia (ie, extremely rapid repetitive discharges that wane from an initially high amplitude). In other cases, a combination of these and other electrical patterns are seen. Perhaps a unique Schwartz-Jampel pattern exists that has not yet been fully defined.

Prior to the discovery of the specific gene defect, the similarity to myotonic disorders provoked speculation that a muscle ion channel abnormality or a muscle enzyme defect might underlie this condition. The fact that a defect exists in the gene for perlecan, a heparin sulfate proteoglycan that is the major proteoglycan of basement membranes and is present in cartilage, supports the general concept of a membrane abnormality and the presence of dysmorphic features. However, precise knowledge of why abnormal electrical discharges occur is still lacking. Perhaps the perlecan abnormality produces secondary membrane channel abnormalities. In addition, how this basement membrane defect actually causes the skeletal and other morphological problems is not understood.

No evidence indicates that the muscle pathology in Stuve-Wiedemann syndrome is similar, although the muscles are probably not normal. Abnormal accumulations of lipid droplets have been found in the muscles of persons with Stuve-Wiedemann syndrome (Di Rocco, 2003), although what this means remains unclear.

Frequency

United States

SJS types IA and IB are very rare, but the frequency is not actually known. Stuve-Wiedemann syndrome is probably even rarer.

International

Although SJS was initially described in the United States, it has also been reported internationally. Both SJS type I and Stuve-Wiedemann syndrome are rare throughout the world

Mortality/Morbidity

• SJS type IA does not significantly shorten lifespan. No definite data exist on whether type IB shortens lifespan. Type II definitely shortens lifespan, with most patients not surviving to adulthood.
• Much of the morbidity of SJS types IA and IB is related to the discomfort associated with the muscle stiffness and to problems with blepharospasm. As many as 20% of affected patients are mentally retarded. However, many patients are of normal or even superior intelligence. Skeletal abnormalities and other physical deformities may cause psychological morbidity in some individuals. Like a number of other myopathies, SJS is associated with an increased risk of malignant hyperthermia.

Race

No significant information is available on racial distribution.

Sex

SJS syndrome has been described in both males and females. However, data are insufficient to indicate any sexual predilection.

Age

SJS is an inherited disease and, thus, it is genetically present from conception. It is usually noticeable by the first year of life and frequently can be diagnosed at or soon after birth.

Clinical

History

• Muscles are clinically stiff and may be hypertrophic, although in some patients muscle mass may be diminished. The dysmorphic features, muscle stiffness, and muscle weakness are usually apparent to the patient's parents during the first year of life and, frequently, soon after birth.
• The stiffness is usually evident when the parents flex the child's limbs.
• The weakness takes the form of delay in achieving motor milestones. For example, walking frequently is delayed. Nevertheless, in most cases, the children do learn to walk and become entirely self-sufficient.
• When they are older, they notice the muscle stiffness, which is usually most severe in the thighs. Patients also report limitations of joint flexion in various joints, particularly the knees.
• Signs include narrow palpebral fissures with normal eyelid development, blepharospasm, and hypertrichosis of the eyelids (ie, excessive hair, multiple rows of hair); micrognathia; unusual flattened facies with a puckered facial appearance; and small muscle mass. Other skeletal and joint deformities include short neck, pectus carinatum (convex chest, ie, chest is bowed out), kyphosis (convex angulation of spine giving a humpback appearance), coxa valga (hip deformity involving increased neck-shaft angle of the femur), and irregularity of capital femoral epiphyses.
• According to one report, the incidence of mental retardation is high (20%), but most patients are of normal intelligence, and high intelligence is not incompatible with this condition.

Physical

• The dysmorphic features are usually evident.
• Most patients are short with narrow palpebral fissures (blepharophimosis), flattened facies, and micrognathia.
• Some patients show blepharospasm in addition to the blepharophimosis.
• Bony abnormalities include joint deformities and limitations of joint motion, coxa valga, irregularity of the capital femoral epiphyses, kyphosis, short neck, and pectus carinatum.
• The muscles are stiff and they can be either hypertrophic or reduced in mass.

Causes

• A multinational collaboration of scientists localized the gene defect for type I SJS to the 1p34-p36 region of chromosome 1 (Nicole, 1995). Further research showed that the specific gene affected was the gene for perlecan, which is a heparin sulfate proteoglycan, the major proteoglycan of basement membranes (Nicole, 2000). It is also involved in cartilage. The gene encoding for perlecan is called HSPG2. Nicole et al described 3 families with a mutation in the HSPG2 gene.
• Types IA and IB both involve a mutation of the perlecan gene.
• The only difference between types IB and IA is that type IB is more severe and, therefore, is usually diagnosed earlier.
• One factor that has impeded the further understanding of SJS type I is that until recently, very few patients had been studied genetically. Through 2005, only 8 patients from 6 families had been reported in molecular genetic studies.
  • Stum et al made a major addition to this literature with a molecular genetic study of 35 patients in 23 families (Stum, 2006). They found 22 new mutations. Most mutations were private (ie, limited to one particular family). Thus, no existence of a founder effect was suggested, whereby all (or a large percentage) of mutations could be presumed to derive from a single original case. The mutations included insertions and deletions and splice-site, missense, and nonsense mutations. Most of the mutations allowed for some level of functional protein production.
  • Often, a given patient has 2 different types of mutations, 1 of which allows a greater production of functional perlecan protein than the other. Based on the cases studied molecularly thus far, some level of functional perlecan protein production always seems apparent. Indeed, through alternative splicing, the normal protein may actually be produced, albeit at a lower level than normal.
  • In other cases, a functional but somewhat abnormal protein may be produced. Alternatively, a combination of different variants of perlecan could be produced, although at lower levels of functional protein than normal.
  • Thus, a significant amount of molecular heterogeneity exists, genomically and proteomically, within SJS type I.
• One would like to think that the molecular heterogeneity could explain the clinical heterogeneity, especially the existence of types IA and IB. In other words, it might be plausible that in type IA, more normal or, at least functional, protein is available than in type IB. So far, however, that has not been shown.
  • In addition, currently no known correlation exists between the specific mutations found and the specific features of a given case. However, the new mutations found by Stum et al in 2006 have been discovered so recently that not enough time has elapsed to explore such possibilities.
  • The new findings should be important tools to help find correlations among genetic variants, perlecan forms and levels, and clinical subtypes. Of course, other facts yet unknown also may influence the severity and the specific characteristics of the disease.
  • The new information does not immediately provide an explanation for the specific character of the problems (ie, the electrical membrane instability of the muscle, the specific dysmorphic features); however, now that many mutations are known, this knowledge can be a basis for future structural and functional correlations to better understand how the perlecan abnormalities cause the features of the disease and, perhaps, to find ways of ameliorating or even curing it.
• An additional molecular biological fact of interest related to perlecan is that another disease, called dyssegmental dysplasia of the Silverman-Handmaker type (DDSH), is also caused by a recessive mutation of the perlecan gene (Arikawa-Hirasawa, 2001). This disease is even rarer than SJS or Stuve-Wiedemann syndrome and even fewer cases have been studied molecularly.
  • In the few that have been studied, mutations that totally eliminate the ability to produce any functional protein product (ie, functionally null mutations) have been discovered. Therefore, whereas in SJS types IA and IB some level of functional (and often even normal) perlecan protein is always produced, in DDSH, none is produced.
  • Conceptually, one could argue that DDSH is a third type of SJS type I (eg, type IC)—the worst type. However, it is considered a separate disease for several reasons.
    • The dysplasia has a segmental quality characterized by significant variations in the shape and size of the vertebral bodies (anisospondyly). This is considered a defect in segmentation during development. This feature has been viewed as making it part of a possible spectrum of dyssegmental disorders, which would include another poorly understood disorder, Rolland-Desbuquois type of dyssegmental dwarfism (Fasanelli, 1985), which is similar to DDSH but somewhat less severe.
    • The dyssegmental dwarfisms also manifest cleft palate and encephalocele, which are not features of SJS. Although the short stature of patients with SJS implies some degree of shortness of limbs, SJS patients do not exhibit the marked limb shortness (micromelia) seen in dyssegmental dwarfism.
  • The issue of whether this is a separate disease is to some extent a question of classification, which could change if more fully studied clinical cases become available. For example, if mutations are found that produce levels of functional perlecan intermediate between those of SJS types I and DDSH and if the phenotype of such patients is also intermediate between the two, then considering them the same disease and just part of a spectrum dependent on the level of expression of functional perlecan would probably be justified. Indeed, no cases of the Rolland-Desbuquois type of dyssegmental dwarfism have been examined for perlecan mutations or for levels of functional perlecan protein expression and it would be very interesting to know whether this variant of dyssegmental dwarfism has a perlecan abnormality.
• Type II is not caused by the same genetic abnormality. The diseased gene in this case was mapped to band 5p13.1 at locus D5S418 (Dagoneau, 2004). By studying the genetic material of 19 patients who had been diagnosed with either Stuve-Wiedemann syndrome or SJS type II, they found that all patients had null mutations in their LIFR gene at the above-mentioned locus. This impaired the function of the JAK/STAT3 signaling pathway. Although the exact mutation was not identical in all 19 patients, the fact that the mutations all appeared to have the same molecular biological and biochemical effect led to the conclusion that Stuve-Wiedemann syndrome and SJS type II should be considered a single homogeneous disease.

Differential Diagnoses

Other Problems to Be Considered

Isaacs syndrome
Malignant hyperthermia
Stuve-Wiedemann syndrome
Becker dystrophy
Blepharospasm, benign essential
Duchenne dystrophy
Myotonic diseases

Workup

Laboratory Studies

• Blood tests: Blood tests may show minor elevations of serum creatine kinase or aldolase. However, in many cases, these enzyme levels are normal. Now that the genes are known, sequencing or polymerase chain reaction studies could be performed, but the specific genes are still not available as tests that can be ordered from a commercial laboratory. Physicians might consider referring suspected cases to genetic clinics that have affiliations with groups actively researching SJS so that genetic studies can be performed.

Imaging Studies

• Imaging studies are of little use. Spine films reveal kyphosis. X-ray films can reveal other skeletal deformities but generally are not necessary for diagnosis.

Other Tests

• EMG and nerve conduction studies
  • The symptoms of muscle stiffness and difficulty relaxing the muscles may prompt EMG and nerve conduction studies.
  • Typically, the nerve conduction findings are normal.
  • The EMG needle study may show continuous discharges. These discharges frequently have the individual appearance of positive sharp waves or fibrillations, but they occur in runs of many discharges.
  • In some cases, the discharges have been described as myotonic, which suggests a waxing and waning character.
  • In other cases, the discharges have not shown waxing or waning. In such cases, they would be considered complex repetitive discharges.

Procedures

• Muscle biopsy: Muscle biopsy findings of patients with SJS are consistent with a myopathy.

Histologic Findings

Minor ultrastructural abnormalities have been described, but no specific electron microscopic signature is known for this disease. Light microscopic findings are usually suggestive of a myopathy. Variation of the muscle fiber size is common. As the individual ages and the disease becomes more advanced, fat and connective tissue may replace muscle fibers.

Treatment

Medical Care

Treatment aims to reduce the abnormal muscle activity that causes stiffness and cramping. For the specific problems of blepharospasm, blepharophimosis, and ptosis, botulinum toxin type A (BTA) (BOTOX®) therapy and surgery may also be considered.

• Nonpharmacologic modalities such as massage, warming, gradually warming-up prior to exercise, and gradual stretching may obviate the need for medications.
• This is a rare condition; the authors know of no controlled trials that have been performed.
• Medications that have been found useful in myotonic disorders, such as the anticonvulsants (eg, phenytoin, carbamazepine) and the antiarrhythmics (eg, mexiletine, procainamide, quinidine, quinine), may be tried.
• Physicians should remember that the muscle stiffness in SJS patients is not life threatening, whereas the adverse effects of these medications can be in some cases. In addition, none of the medications mentioned is approved specifically for this disease, with the exception that "skeletal muscle hyperactivity" is listed as part of the category information for quinine.
• Administering via any route other than oral is not advisable when using these medications to treat muscle stiffness associated with SJS or similar conditions. The patient should be monitored carefully for possible development of the listed adverse effects. Specifically, patients who are to receive antiarrhythmics or quinine should have no significant cardiac conduction abnormality or tendency toward any conduction abnormality. Consultation with a cardiologist should be strongly considered when prescribing these medications.
• BOTOX® injections reportedly yielded good results for relieving blepharospasm in 2 sisters with SJS (Vargel, 2006). The authors proceeded slowly and carefully, individualizing the treatment to the needs of the patients. They initially administered a total of 25 units in the orbicularis oculi of each eye. This provided no significant relief. After waiting 6 months, they doubled the dose. This began to provide relief. After waiting another 6 months, they again administered 50 units to the orbicularis oculi of each eye and the patient obtained significant cosmetic and functional improvement. Because ptosis can also be a problem in SJS patients and because BOTOX® can produce ptosis, one must proceed very carefully. Interestingly, another report indicated that giving BOTOX® just to the lower eyelid muscles had the effect of widening the aperture of the eye in persons with this condition (Flynn, 2001).

Surgical Care

For cases of blepharospasm, ptosis, and other difficulties maintaining a sufficiently wide-open eye, if BOTOX® does not work, a variety of surgical techniques have been used effectively, including orbicularis oculi myectomy, levator aponeurosis resection, and lateral canthopexy. A 2006 article describes some surgical approaches and provides additional references (Morrison, 2006).

Medication

For additional information on pharmacodynamics or pharmacokinetics of the drugs discussed in this section, standard pharmacologic references such as Drug Facts and Comparisons (Walters Kluwer, St. Louis, Mo), Mosby's GenRx (Mosby, St. Louis, Mo), Physicians Desk Reference (Medical Economics Company), or the package insert should be consulted.

Anticonvulsants

Although the primary use of anticonvulsants is to decrease excessive neuronal discharges seen in epileptic seizures, some of them appear to also reduce excess muscle cell depolarization. The fundamental mechanism in both cases may be the anticonvulsants' ability to reduce the activity of ion channels in the cell membrane. They are used widely in central pain syndromes. Their use to reduce muscle spasm and cramps is largely empirical and they are not approved by the US Food and Drug Administration for this purpose.

Phenytoin (Dilantin)

As an anticonvulsant, phenytoin reduces the rate at which neurons fire by stabilizing the inactive form of neuronal sodium channels and by blocking L-type neuronal calcium channels. May affect similar channels in muscle to reduce muscle contraction.

Dosing

Adult

Seizures: 300 mg/d PO typically recommended; some authorities give maximum of 5 mg/kg/d PO If muscle contractions trouble patient at night, 100 mg hs may be sufficient; sometimes as much as 300 mg can be given as single dose hs; in other cases, must be given bid/tid

Pediatric

Seizures: 5 mg/kg/d PO bid/tid
Muscle irritability: 30 mg PO either hs or during day when child is most troubled by muscle contractions; gradually increase to 4-8 mg/kg/d divided bid/tid; if effective at low dose, do not increase dosage

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity
Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects
May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid

Contraindications

Documented hypersensitivity; Stokes-Adams syndrome; significant cardiac rhythm disturbances (eg, sinus bradycardia, sinoatrial block, second- or third-degree AV block)

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Death from cardiac arrest after too-rapid IV administration may occur (sometimes preceded by marked QRS widening)
Caution in acute intermittent porphyria and diabetes; discontinue drug if hepatic dysfunction occurs Can provoke reactions in several specific systems or organs, including CNS (eg, nystagmus, ataxia, slurred speech, confusion, dizziness), cardiovascular (eg, cardiac collapse, hypotension), GI (various disturbances), gingival hyperplasia, connective-tissue abnormalities, hepatitis and other liver damage, skin (rashes, other problems), endocrine (eg, increase in blood glucose, diabetes insipidus), genitourinary, hematological, respiratory, special senses, and musculoskeletal (including osteoporosis)
Perform CBC counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias
Discontinue use if rash appears; if rash is exfoliative, bullous, or purpuric, do not resume use

Carbamazepine (Tegretol)

Chemical analogue of TCAs and was first developed for depression. Was found to be useful for relief of pain in depression. Used for trigeminal neuralgia. Because trigeminal neuralgia is caused by rapid firing of nerves, it was next tried for rapid neuronal firing seen in seizures and proved very effective. Like phenytoin, probably works by inhibiting neuronal sodium channels and may have direct effects on neurotransmitter systems.
May inhibit sodium channels or other ion channels in muscle. Adult dose similar to that used in pain syndromes.

Dosing

Adult

100 mg PO bid initially; increase gradually to 200 mg PO tid/qid if tolerated

Pediatric

<6 years: 10-20 mg/kg/d PO
6-12 years: 10 mg/kg/d PO initially; increase to 20-30 mg/kg/d PO divided bid/qid
If susp (liquid) form used, smaller, more frequent doses are better tolerated (ie, tid/qid)

Interactions

Danazol within last 30 d may significantly increase serum levels (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels)

Contraindications

Documented hypersensitivity; history of bone marrow depression; MAOIs within last 14 d

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum iron at baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Antiarrhythmic agents

Cardiac antiarrhythmics reduce or regulate the firing rate of cardiac cells by a number of mechanisms, the most precisely understood of which are effects on ion channels. That a similar effect may occur in the skeletal muscle should not be surprising. Of the antiarrhythmics, mexiletine is probably the most commonly used for this condition. Procainamide and quinidine also have been listed for completeness and because they are used by many neurologists to treat muscle stiffness and muscle spasm. Quinine also can be useful occasionally. Quinine should be classified as an antiarrhythmic because of its similarity to quinidine. However, the most recent classifications list it under "antimalarials, antiprotozoals, skeletal muscle hyperactivity." It is therefore discussed under that category.

Mexiletine (Mexitil)

As class IB antiarrhythmic, preferentially binds to open or inactivated calcium channels with rapid association rate. Binding to open channels effectively shortens action potential (particularly third phase) and binding to inactivated channels maintains inactivated (refractory) state. This slows firing of cells. Presumably, similar effect may occur in skeletal muscle.

Dosing

Adult

200 mg PO tid initially; increase dose by 50 or 100 mg q2-3d until 300 mg tid reached; sometimes as much as 400 mg tid used
Muscle stiffness and spasm: 150 mg PO tid initially; not advisable to increase dose to >300 mg tid

Pediatric

Not established

Interactions

Aluminum-magnesium hydroxide compounds, atropine, narcotics, hydantoins, rifampin, and urinary acidifiers may decrease levels; metoclopramide and urinary alkalinizers may increase levels; cimetidine can either increase or decrease levels; may increase levels of caffeine and theophylline

Contraindications

Documented hypersensitivity; cardiogenic shock; second- or third-degree AV block (without pacemaker)

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Second- or third-degree AV block (without pacemaker) is contraindication; can be used cautiously in patients with second- or third-degree AV block with pacemaker, first-degree AV block, sinus node dysfunction, intraventricular conduction abnormalities, hypotension, or congestive heart failure (consultation with cardiologist recommended before using this medication in any of these medical conditions)
Liver injury reported, particularly in conjunction with congestive heart failure or cardiac ischemia—monitor liver enzymes; leukopenia or agranulocytosis occur rarely—CBC count should be monitored; convulsions have occurred in approximately 0.2% of patients, thus, caution indicated if patient has history of seizures; avoid other drugs that significantly modify urine pH

Procainamide (Procanbid, Pronestyl)

As class IA antiarrhythmic, blocks open or inactivated sodium channels with slower association rate than class IB drugs (eg, mexiletine). This slows depolarization phase (phase 0) of action potential and prolongs overall action potential, thus decreasing firing rate. Presumably similar effect may occur in skeletal muscle.
Has been listed because included in discussions of muscle stiffness or muscle spasm. Has never been prescribed by authors for this condition. If used for muscle stiffness, then cardiac dosing regimen should be used, starting with short-acting form. This is replaced with equivalent amount of long-acting form once medication has proven effective and is well tolerated.

Dosing

Adult

Cardiac arrhythmia: 50 mg/kg/d IV q3-6h, with total dose and interval adjusted according to patient response; 250 mg IV q3h of standard form is equivalent to 500 mg q6h of SR form
Muscle stiffness: 250-500 mg IV qid

Pediatric

Not established

Interactions

Cimetidine, ranitidine, beta-blockers, amiodarone, trimethoprim, and quinidine increase levels of procainamide metabolite NAPA; may increase effect of skeletal muscle relaxants quinidine and lidocaine and neuromuscular blockers; ofloxacin inhibits tubular secretion and may increase bioavailability; sparfloxacin may increase risk of cardiotoxicity

Contraindications

Documented hypersensitivity; second- or third-degree heart block, if pacemaker not in place; torsade de pointes; systemic lupus erythematosus

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Monitor for hypotension; plasma concentrations of procainamide and active metabolite, NAPA, may increase in renal failure; high or toxic concentrations may induce AV block or abnormal automaticity; caution in complete AV block, digitalis intoxication, organic heart disease, renal disease, and hepatic insufficiency

Quinidine (Cardioquin, Quinora)

As class IA antiarrhythmic, blocks open or inactivated sodium channels with slower association rate than class IB drugs (eg, mexiletine). This slows depolarization phase (phase 0) of action potential and prolongs overall action potential, thus decreasing firing rate. Presumably similar effect may occur in skeletal muscle.
For SJS, only PO administration known to be used. Use of any other mode of administration is not advised.

Dosing

Adult

200 mg PO test dose administered with observation for idiosyncratic reactions
Premature atrial and ventricular contractions: 200-300 mg PO tid/qid

Pediatric

Not established

Interactions

Phenytoin, rifampin, and phenobarbital may decrease concentrations; ritonavir, sparfloxacin, beta-blockers, amiodarone, verapamil, cimetidine, alkalinizing agents, or nondepolarizing and depolarizing muscle relaxants may increase toxicity; may enhance effect of anticoagulants

Contraindications

Documented hypersensitivity; complete AV block or intraventricular conduction defects; concurrent ritonavir or sparfloxacin

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia; avoid use in myocardial depression, hepatic or renal insufficiency, and myasthenia gravis

Antimalarials, antiprotozoals, skeletal muscle hyperactivity

The only drug in this category generally used to relieve muscle stiffness is quinine. Quinine appears to increase the refractory period for muscle discharge, exerts a curarelike action on the motor endplate, and alters the intracellular calcium distribution in a way that makes the muscle less excitable.

Quinine sulfate (Formula Q)

Actually an optical isomer of quinidine and, like quinidine, belongs to cinchona alkaloid group of drugs. Also has effects on heart similar to those of quinidine and, thus, is subject to similar cautions. Available in 260-, 300-, and 325-mg cap. Any of these can be given as hs dose for nocturnal muscle stiffness.

Dosing

Adult

Administer up to 650 mg PO tid; authors have not prescribed >300 mg tid for off-label use in muscle stiffness

Pediatric

Not established

Interactions

Aluminum-containing antacids may delay or decrease bioavailability; cimetidine increases blood levels and creates potential for toxicity; rifamycins decrease concentrations by increasing hepatic clearance (effect can persist for several days after discontinuing rifamycins); acetazolamide or sodium bicarbonate may increase toxicity by increasing blood levels; may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K–dependent clotting factors; may increase digoxin serum concentrations—important to monitor digoxin levels periodically; may decrease plasma cholinesterase activity, causing decrease in metabolism of succinylcholine

Contraindications

Documented hypersensitivity; optic neuritis; tinnitus; G-6-PD deficiency; history of black water fever

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing may cause cinchonism; quinine has quinidinelike activity and thus can cause cardiac arrhythmias

Neuromuscular blocking agents

Indicated for blepharospasms associated with SJS.

Botulinum toxin type A (BOTOX®)

One of several toxins produced by Clostridium botulinum. Blocks neuromuscular transmission through a 3-step process, as follows:
(1) blockade of neuromuscular transmission; BTA binds to motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals.
(2) BTA is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal.
(3) BTA blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. Toxin does not affect
synthesis or storage of acetylcholine or conduction of electrical signals along the nerve fiber.
Typically, a 24-72 h delay occurs between administration of toxin and onset of clinical effects, which terminate in 2-6 mo. This purified neurotoxin complex is a vacuum-dried form of purified BTA, which contains 5 ng of neurotoxin complex protein per 100 U. Treats excessive, abnormal contractions associated with blepharospasm.
BTA must be reconstituted with 2 mL of 0.9% sodium chloride diluent. With this solution, each 0.1 mL results in 5 U dose. Patient should receive 5-10 injections per visit. Must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative using manufacturer's instructions to provide injection volume of 0.1 mL; must be used within 4 h of storage in refrigerator at 2-8°C. Preconstituted dry powder must be stored in freezer at <5°C. Reexamine patients 7-14 d after initial dose to assess for response. Increase doses 2-fold over previous one for patients experiencing incomplete paralysis of target muscle. Do not exceed 25 U when giving it as single injection or 200 U as cumulative dose in 30-day period.

Dosing

Adult

25 U per eye divided into 4-6 periocular injection sites (2.5-10 U/site) may avoid adverse effects; lower volumes (higher concentrations) suggested to avoid risk of spread to adjacent areas; adjust subsequent treatments depending on response to initial doses (eg, Vargel et al increased to 50 U per eye 6 mo later when 25 U did not work); note that the 6-mo waiting period between treatment is important to reduce chances that patient develops antibodies to BTA

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Aminoglycosides or drugs that interfere with neuromuscular transmission may potentiate effects of BTA

Contraindications

Documented hypersensitivity; infection present at injection site

Precautions

Pregnancy

Precautions

Do not exceed recommended dosages and frequencies of administration; presence of antibodies to BTA may reduce effects of therapy; when used for cervical dystonia may cause dysphagia, upper respiratory tract infection, neck pain, or headache; ptosis may occur when used for blepharism or strabismus; weakness of hand muscles and blepharoptosis may occur when used for palmar or facial hyperhidrosis, respectively When used cosmetically for glabellar lines, may cause headache, respiratory tract infection, flulike syndrome, blepharoptosis, or nausea

Follow-up

Prognosis

• Except for the patients with Stuve-Wiedemann syndrome, which is fundamentally a different disease, most patients have a good prognosis.
• Muscle stiffness, muscle weakness, and skeletal abnormalities may worsen gradually or remain essentially stable.

Patient Education

• Because patients with SJS have a characteristic physical appearance, they may need extra psychosocial support.
• As in all diseases causing muscle stiffness, the danger exists of iatrogenic addiction to muscle relaxants such as diazepam (which is not particularly useful in this condition).
• If patients are treated with the medications listed in this article or with other medications, they should be educated about the adverse effects.
• The subset (as many as 20%) of patients who also have mental retardation require special education for that problem.

Miscellaneous

Medicolegal Pitfalls

• The tendency to malignant hyperthermia could lead to adverse outcomes in surgery.
• Cosmetic surgery to relieve the blepharospasm, blepharophimosis, and ptosis carries a medicolegal risk.

References

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Keywords

Schwartz Jampel syndrome, chondrodystrophic myotonia, myotonic myopathy, dwarfism, chondrodystrophy, ocular and facial anomalies, Schwartz-Jampel-Aberfeld syndrome, SJA syndrome, SJS

Contributor Information and Disclosures

Author

Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center
Stephen A Berman, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Eric Dinnerstein, MD, Consulting Staff Neurologist, Maine Neurology
Eric Dinnerstein, MD is a member of the following medical societies: American Academy of Neurology and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Daniel H Jacobs, MD, Clinical Associate Professor, Department of Neurology, University of Florida
Daniel H Jacobs, MD is a member of the following medical societies: American Academy of Neurology, American Society of Neurorehabilitation, and Society for Neuroscience
Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex Grant/research funds Independent contractor; Serono EMD Royalty Speaking and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Agapito S Lorenzo, MD, Laboratory Director, Associate Professor, Departments of Neurology, Creighton University and University of Nebraska Medical Center
Agapito S Lorenzo, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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