Schwartz-Jampel syndrome (SJS) is a term now applied to 2 different inherited, autosomal recessive 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. (See Etiology.)
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."[1] In this paper, the authors presented the case of 2 siblings, a boy aged 6 years and a girl aged 3.5 years, who had the following clinical characteristics (see Presentation):
Electromyography (EMG) was not performed. The authors proposed that the disease might represent a generalized problem with muscle and tendon development during infancy.
The clinical features of muscle stiffness in SJS type I somewhat resemble those seen in myotonic disorders, stiff person syndrome, and 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). (See Presentation.)
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. (See Workup.)
In affected patients with type I, 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. SJS types IA and IB derive from mutations of the same gene, the HSPG2 gene, which codes for perlecan, a heparin sulfate proteoglycan.
Type IA
The most commonly recognized and described form of SJS is type IA, which exhibits muscle stiffness, mild (and largely nonprogressive) muscle weakness, and a number of minor morphologic abnormalities. Type IA is the classic type described by Schwartz and Jampel. It becomes apparent later in childhood and is less severe than type IB. (See Presentation.)
Type IB
Type IB is apparent immediately at birth and is clinically more severe, although it is typically compatible with life and even long-term survival.
SJS type II, like type IB, is apparent immediately at birth. The patients look similar to those with type IB. However, it has been 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. (See Etiology.)
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). (See Presentation.)[2]
A high infant mortality rate is associated with this condition. Long-term survivors are rare but do exist, including 2 survivors, ages 3 and 12 years, reported on by Di Rocco et al in 2003.[3] In addition to problems with bone dysplasia, these 2 children 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). Reither et al reported on a survivor aged 16 years with SJS type II. (See Prognosis.)[4]
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 in this article pertains to SJS types IA and IB. Information pertinent to Stuve-Wiedemann syndrome will be identified as such.
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 drugs’ adverse effects. (See Treatment and Medication.)
Prior to the discovery of the specific gene defect in SJS, the syndrome’s 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 as to 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 morphologic problems is not understood.
No evidence indicates that the muscle pathology in Stuve-Wiedemann syndrome is similar to that in SJS type I, although the muscles are probably not normal. Abnormal accumulations of lipid droplets have been found in the muscles of persons with Stüve-Wiedemann syndrome,[3] although what this means remains unclear.
A multinational collaboration of scientists localized the gene defect for type I SJS to the 1p34-p36 region of chromosome 1.[5] 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.[6] 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.
Although SJS types IA and IB both involve a mutation of the perlecan gene, type IB is a more severe condition and, therefore, is usually diagnosed earlier than type IA.
One factor that has impeded the further understanding of SJS type I is that until the early 21st century, 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, finding 22 new mutations.[7] 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 more functional, protein is available than in type IB. So far, however, that has not been shown.
In addition, no correlation has yet been found between the specific mutations found and the specific features of a given case. However, the findings by Stum et al 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.
Although the mutations discovered by Stum et al do not immediately provide an explanation for the specific character of the problems found in SJS (ie, the electrical membrane instability of the muscle, the specific dysmorphic features), 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, SJS.
A study by Rodgers et al questioned the concept that the C1532 mutation is the sole causative factor in SJS. The investigators developed perlecan knock-in mice to model SJS. The authors suggested that the transcriptional changes leading to perlecan reduction may represent the disease mechanism for SJS.[8]
A study by Stum et al concluded that partial endplate acetylcholinesterase (AChE) deficiency may contribute to muscle stiffness.[9] However, this deficiency was not associated with spontaneous activity at rest on EMG in the diaphragm, suggesting that there are additional factors that are required to generate the activity seen in SJS.
Dyssegmental dysplasia of the Silverman-Handmaker type
An additional point 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.[10] This disease is even rarer than SJS or Stuve-Wiedemann syndrome, and even fewer cases have been studied molecularly.
In the few patients who 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 form 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 condition, Rolland-Desbuquois type of dyssegmental dwarfism[11] ; this disorder is similar to, but somewhat less severe than, DDSH.
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 DDSH 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 2, 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.
However, no cases of the Rolland-Desbuquois type of dyssegmental dwarfism have been examined for perlecan mutations or for levels of functional perlecan protein expression.
SJS type II is not caused by the same genetic abnormality as SJS type I. The diseased gene in type II has been mapped to band 5p13.1, at locus D5S418.[12] By studying the genetic material of 19 patients who had been diagnosed with either Stuve-Wiedemann syndrome or SJS type II, investigators 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 biologic and biochemical effect led to the conclusion that Stuve-Wiedemann syndrome and SJS type II should be considered a single, homogeneous disease.
SJS types IA and IB are very rare in the United States, although the exact frequency of these disorders is not known. Stuve-Wiedemann syndrome is even rarer. Although SJS was initially described in the United States, it has also been reported internationally, but as in the United States, SJS type I and Stuve-Wiedemann syndrome are rare throughout the world. About 150 cases of SJS have been reported in the medical literature.
SJS syndrome has been described in males and females. However, data are insufficient to indicate any sexual predilection. Because SJS is an inherited disease, 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.
Except for the patients with Stuve-Wiedemann syndrome, which is fundamentally a different disease from SJS type I, most patients with SJS have a good prognosis. Muscle stiffness, muscle weakness, and skeletal abnormalities may worsen gradually or remain essentially stable.
SJS type IA does not significantly shorten lifespan. No definite data exist on whether this is also true for 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.
The parents of patients with Schwartz-Jampel syndrome (SJS) usually note dysmorphic features, muscle stiffness, and muscle weakness, frequently soon after birth or within the first year of life. They may report that their child's muscles are stiff and hypertrophic.
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, patients 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 of SJS also include the following:
Skeletal and joint deformities include the following:
According to one report, the incidence of intellectual disability in patients with SJS is high (25%). However, most patients are of normal intelligence, and high intelligence is not incompatible with this condition. Poor speech articulation and drooling is common so affected individuals can be misdiagnosed as having intellectual disability.
The dysmorphic features of SJS are usually evident on physical examination. Most patients are short with narrow palpebral fissures (blepharophimosis), flattened facies, and micrognathia. Some patients show blepharospasm in addition to the blepharophimosis. The muscles are stiff and they can be either hypertrophic or reduced in mass.
Bony abnormalities include the following:
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 (PCR) assay 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 are of little use. Spinal films reveal kyphosis. Radiographs can reveal other skeletal deformities but generally are not necessary for diagnosis.
Muscle biopsy findings of patients with SJS are consistent with a myopathy.
Minor, ultrastructural abnormalities have been described in SJS, but no specific electron microscope signature is known for the disorder. Light microscope findings are usually suggestive of a myopathy. Variations in muscle fiber size are common. As the individual ages and the disease becomes more advanced, fat and connective tissue may replace muscle fibers.
The symptoms of muscle stiffness and of difficulty relaxing the muscles may prompt EMG and nerve conduction studies in a patient. Typically, the nerve conduction findings are normal.[13]
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.
The treatment of Schwartz-Jampel syndrome (SJS) aims to reduce the abnormal muscle activity that causes stiffness and cramping. Treatment may include nonpharmacologic modalities, medication (including botulinum toxin [BOTOX®]), or surgery. No controlled trials have investigated the efficacy of these treatments, but case reports have demonstrated treatment success with BOTOX® and surgery.
Nonpharmacologic modalities and strategies such as massage, warming, gradual warm-up prior to exercise, and gradual stretching may obviate the need for medications.
If the administration of BOTOX® does not work for cases of blepharospasm, ptosis, and other difficulties maintaining a sufficiently wide-open eye, a variety of surgical techniques have been used effectively, including orbicularis oculi myectomy, levator aponeurosis resection, and lateral canthopexy.[14] (The tendency for malignant hyperthermia to occur in SJS could lead to adverse outcomes in surgery.)[15, 16, 17]
Medications that have been found useful in myotonic disorders, such as anticonvulsants (eg, phenytoin, carbamazepine) and antiarrhythmics (eg, mexiletine, procainamide, quinidine, quinine), may be tried in SJS. None of the medications mentioned are approved specifically for this disease, with the exception that "skeletal muscle hyperactivity" is listed as part of the category information for quinine.
Administering these drugs via any route other than oral is not advisable when they are used to treat muscle stiffness associated with SJS or similar conditions. The patient should be monitored carefully for possible development of the listed adverse effects. Moreover, 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.[18] The authors proceeded slowly and carefully, individualizing the treatment to the needs of the patients. They initially administered a total of 25U in the orbicularis oculi of each eye. This provided no significant relief. After waiting 6 months, they doubled the dose, and this began to provide relief. After waiting another 6 months, they again administered 50U 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.[19]
Surgery may be an option for SJS patients to help treat and/or correct musculoskeletal abnormalities including joint contractures, kyphoscoliosis, and hip dysplasia. For some, surgery combined with physical therapy may help improve the ability to walk and perform other movements independently. Comprehensive dental treatment is also often required as well.[20]
Use of general anesthesia in patients with SJS may be dangerous for risk of malignant hyperthermia exists.[20]
Medications used in the treatment of Schwartz-Jampel syndrome (SJS) include the following:
Some anticonvulsants appear to reduce excess muscle cell depolarization, while the antiarrhythmics may reduce or regulate the firing rate of skeletal muscle cells, much as they do in cardiac cells. BOTOX® blocks neuromuscular transmission through a multistep process.
The antimalarial drug 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.
Clinical Context: 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. It may affect similar channels in muscle to reduce muscle contraction.
Clinical Context: Carbamazepine is a chemical analogue of tricyclic antidepressants (TCAs) and was first developed for depression. It was found to be useful for the relief of pain in depression, and it is used for trigeminal neuralgia. Because trigeminal neuralgia is caused by the rapid firing of nerves, carbamazepine was next tried for rapid neuronal firing seen in seizures and proved very effective. Like phenytoin, carbamazepine probably works by inhibiting neuronal sodium channels and may have direct effects on neurotransmitter systems.
Carbamazepine may inhibit sodium channels or other ion channels in muscle. The adult dose is similar to that used in pain syndromes.
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. Anticonvulsants 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 (FDA) for this purpose.
Clinical Context: As a class IB antiarrhythmic, mexiletine preferentially binds to open or inactivated calcium channels with a rapid association rate. Binding to open channels effectively shortens the action potential (particularly the third phase), and binding to inactivated channels maintains the inactivated (refractory) state. This slows the firing of cells. Presumably, a similar effect may occur in skeletal muscle.
Clinical Context: As a class IA antiarrhythmic, procainamide blocks open or inactivated sodium channels with a slower association rate than class IB drugs (eg, mexiletine). This slows the depolarization phase (phase 0) of the action potential and prolongs the overall action potential, thus decreasing the firing rate. Presumably, a similar effect may occur in skeletal muscle.
Procainamide has been listed here because it has been included in discussions of muscle stiffness and muscle spasm. It has never been prescribed by authors for this condition. If it is used for muscle stiffness, then the cardiac dosing regimen should be used, starting with the short-acting form. This is replaced with an equivalent amount of the long-acting form once the medication has proven effective and is well tolerated.
Clinical Context: As a class IA antiarrhythmic, quinidine blocks open or inactivated sodium channels with a slower association rate than class IB drugs (eg, mexiletine). This slows the depolarization phase (phase 0) of the action potential and prolongs the overall action potential, thus decreasing the firing rate. Presumably, a similar effect may occur in skeletal muscle.
For SJS, only oral administration of quinidine is known to be used. The use of any other mode of administration is not advised.
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 here 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." It is therefore discussed under that category.
Clinical Context: Quinine is actually an optical isomer of quinidine; like quinidine, it belongs to the cinchona alkaloid group of drugs. Quinine has effects on the heart similar to those of quinidine and, thus, is subject to similar cautions. Quinine is available in 260-, 300-, and 325-mg capsules. Any of these can be given as a bedtime dose for nocturnal muscle stiffness.
The only drug in this category that is 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.
Clinical Context: This is one of several toxins produced by Clostridium botulinum. It blocks neuromuscular transmission through a 3-step process.
Step 1
BOTOX® binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals.
Step 2
BOTOX® 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 the 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.
Step 3
BOTOX® 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. The toxin does not affect the synthesis or storage of acetylcholine or the conduction of electrical signals along the nerve fiber.
Typically, a 24- to 72-hour delay occurs between the administration of toxin and the onset of clinical effects, which terminate in 2-6 months. This purified neurotoxin complex is a vacuum-dried form of purified botulinum toxin A, which contains 5 ng of neurotoxin complex protein per 100 U. It treats excessive, abnormal contractions associated with blepharospasm.
BOTOX® must be reconstituted with 2 mL of 0.9% sodium chloride diluent. With this solution, each 0.1mL results in a 5-U dose. The patient should receive 5-10 injections per visit. BOTOX® must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative, using the manufacturer's instructions, to provide an injection volume of 0.1 mL. It must be used within 4 hours of storage in a refrigerator at 2-8°C. Preconstituted dry powder must be stored in a freezer at below 5°C.
Reexamine patients 7-14 days after the initial dose of BOTOX® to assess for a response. Increase the dose 2-fold over the previous one for patients experiencing incomplete paralysis of the target muscle. Do not exceed 25 U when giving BOTOX® as single injection or 200 U as a cumulative dose in a 30-day period.
Agents in this class cause presynaptic paralysis of the myoneural junction and reduce abnormal contractions. BOTOX® is indicated for blepharospasms associated with SJS.