Abstract
Mucopolysaccharidoses are lysosomal storage disorders that are caused by a deficiency in the enzymes that degrade glycosaminoglycans. The accumulation of glycosaminoglycans affects multiple systems, resulting in coarse facial features, short stature, organomegaly, and variable neurological changes from normal intelligence to severe mental retardation and spasticity. Effects on the musculoskeletal system include dysostosis multiplex, joint stiffness, and muscle shortening. This article reports 2 patients with mucopolysaccharidosis type II (Hunter syndrome) who showed progressive equinus deformity of the feet. Both patients were treated with intramuscular botulinum toxin type A injections in the gastrocnemius and the soleus muscles, followed by serial casting. In both patients, passive range of motion, muscle tone, and gait performance were significantly improved. Botulinum toxin type A injections followed by serial casting are a therapeutic option for contractures in patients with mucopolysaccharidosis. However, the long-term effects and the effect of application in other muscles remain unknown.
The mucopolysaccharidoses are a group of lysosomal storage disorders that are caused by a deficiency in enzymes that are required for the breakdown of glycosaminoglycans. Hence, the enzyme defects lead to an accumulation of partially degraded glycosaminoglycans in the lysosomes. Hunter syndrome, also known as mucopolysaccharidosis type II, is a rare X-linked disorder with an incidence of 1:170 000 male live-births. 1 Rare cases of affected females have also been reported. Hunter syndrome is caused by a deficiency in iduronate 2-sulfatase, which leads to a multisystemic accumulation of 2 glycosaminoglycans, heparan sulfate and dermatan sulfate. The gene that encodes iduronate 2-sulfatase is located at Xq27.3-q28. To date, no precise genotype–phenotype correlation has been determined. 2 Patients have a normal appearance at birth and generally present with their first symptoms between 18 months and 6 years of age.1,3,4 The progressive changes in the multiple systems involved include coarse facial features, macroglossia, short stature, cardiac involvement, organomegaly, neurological disorders with mental retardation and spasticity, and disorders of the musculoskeletal system. Death usually occurs in the second decade of life due to cardiac or respiratory failure. Patients with an attenuated phenotype can have normal intelligence and survive into adulthood.1,4,5
In mucopolysaccharidosis type II, skeletal and connective tissue complications include dysostosis multiplex and can lead to significant physical impairment due to macrocephaly, prematurely closed sutures, imperfect teething, irregularly shaped and thickened long bones, pelvic abnormality, and the deformity of the ribs and the spine, which results in kyphosis and scoliosis. 6 In combination with the accumulation of glycosaminoglycans in the trachea, spinal deformity can lead to reduced thoracic expansion and airway obstruction. 7 Progressive cervical myelopathy caused by a narrowed spinal canal due to dysostosis multiplex and pachymeningitis cervicalis is common in patients with mucopolysaccharidosis type II. Clinically, patients can present with increasing spasticity and/or urinary retention that is secondary to neurogenic bladder.8,9 Gibbus deformity and/or atlantoaxial subluxation can aggravate the spinal canal stenosis.8,10,11 In addition to regular clinical examination, the recommendations for the multidisciplinary management of mucopolysaccharidosis type II include magnetic resonance imaging (MRI) of the cervical spine at 1- to 3-year intervals to rule out spinal stenosis and myelopathy in patients with mucopolysaccharidosis type II. 3
In addition, patients with mucopolysaccharidosis type II suffer from progressive joint stiffness, which has been shown to lead to a significant limitation in the range of motion and decreased gross motor abilities. 6 Until recently, there had been no effective therapy for treating mucopolysaccharidosis type II. Enzyme replacement therapy using recombinant human iduronate-2-sulfatase was introduced in 2006. Weekly intravenous infusions of idursulfase improve many symptoms, especially if started early.5,12 Although the detailed impact of enzyme replacement therapy on skeletal abnormalities is not known, the improvement of soft-tissue contractures has been reported in some patients. 3 In addition to being treated with enzyme replacement therapy, musculoskeletal problems in patients with mucopolysaccharidosis type II are treated with regular physical therapy regimens and orthopedic surgery. 6 Nevertheless, progressive worsening of joint contractures often results in immobilization and wheelchair dependence. Intramuscular injections of botulinum toxin type A represent a well-established option for the treatment of joint contractures in patients with spastic cerebral palsy.13 –16
Few studies have examined botulinum toxin type A treatment in patients with mucopolysaccharidosis. A Spanish group showed a positive effect of botulinum toxin type A treatment in the psoas muscle in a patient with mucopolysaccharidosis type III. 17 We describe 2 patients with mucopolysaccharidosis type II who presented with progressive equinus deformity and were treated with intramuscular botulinum toxin type A followed by serial casting.
Case Reports
Case 1
The patient was referred at the age of 28 months because of developmental delay and behavioral problems. The neurological examination revealed truncal hypotonia, slightly elevated muscle tone in the lower extremities with exaggerated tendon jerks, and a tendency for an equinus gait. Furthermore, frontal bossing and a coarse face with padded lips as well as mild flexion contractures of the elbows were observed. Moreover, the patient presented with a marked hepatosplenomegaly. Radiographs showed an ovoid configuration of the vertebra in the lumbar and the thoracic spine and a conic proximal pointing of the ossa metacarpalia II-V. Urinary glycosaminoglycans excretion was elevated, and iduronate 2-sulfatase enzyme activity was reduced to 10% in leukocytes. Furthermore, a complete exon 7 deletion in the iduronate 2-sulfatase gene was found that genetically confirmed the diagnosis of mucopolysaccharidosis type II. An MRI scan of the brain showed a slight retardation of the periventricular and the dorsal white matter and a mild atlantooccipital dislocation with enlarged soft tissue.
In the following 2 years, the patient developed progressive joint stiffness and decreased range of motion in the ankles and elbows. Enzyme replacement therapy with idursulfase was initiated at the age of 4 years and 9 months. However, equinus deformity increased, and the patient’s gait performance deteriorated. Spinal stenosis and cervical myelopathy were ruled out by a regular MRI of the cervical spine every 2 years.
3
He was treated with regular physical therapy and ankle–foot orthoses. At 6 years and 10 months of age, wearing the ankle–foot orthoses became painful because of the progressive nature of the equinus deformity. The patient was able to walk without assistive devices for a maximal distance of 100 m. However, for longer distances, he required a wheelchair. His gait pattern was characterized by bilateral forefoot landing, and there was no complete foot contact in the stance phase. There was a slight knee flexion during midstance. Orthopedic examination of the lower limbs showed bilateral hip flexion contracture (Thomas test of 10°), slight knee flexion contractures (5° deficit bilaterally), and profound equinus deformity in the ankle (ankle dorsiflexion with bended knees, 5° right, 0° left; ankle dorsiflexion with extended knees, –15° bilaterally). There were no signs of spasticity (defined as a velocity-dependent increase of the tonic stretch response)
18
; however, bilateral rigidity of his gastrocnemius and soleus muscles was observed.
We performed intramuscular botulinum toxin type A injections to increase the patient’s range of motion, eliminate pain when wearing of the ankle–foot orthoses, improve gait performance, and prevent further contractures. The parents gave oral informed consent for this off-label use of botulinum toxin type A. The treatment was performed using general anesthesia. Bilateral injections in the soleus muscle and in the medial and the lateral head of the gastrocnemius muscle were performed using the electrophysiological guidance of a nerve stimulator (Stimuplex, B. Braun, Melsungen, Germany). A total dosage of 280 U of botulinum toxin type A (Botox, Allergan, Irvine, USA) corresponding to 10.3 U per kilogram of body weight was injected using a dilution of 50 U of botulinum toxin type A per milliliter of 0.9% sodium chloride (M soleus: 2 injection sites per muscle, 2 × 20 U; medial and lateral head of the M gastrocnemius: 2 injection sites per muscle, 2 × 25 U). Recovery after anesthesia was uneventful.
After the intervention, new ankle–foot orthoses were manufactured, and intensified physical therapy (3 times weekly), which included gait training and stretching, was prescribed. According to the child’s parents, muscle tone was reduced in the second week after the intervention, which resulted in an improved foot–floor contact pattern during the gait. Two weeks after the intervention, a regression cast was placed on both ankles. However, the regression cast was not tolerated by the patient and required removal after 1 week. Three weeks after the intervention, there was an increased range of motion in the ankle joint, which permitted wearing of the new ankle–foot orthoses without discomfort. A regular clinical assessment was performed 2 months after the treatment, which showed an increased range of motion of the ankles in the orthopedic examination (ankle dorsiflexion with extended knees 0° bilaterally). Six months after the botulinum toxin type A treatments, the contractures exhibited slight reoccurrence (ankle dorsiflexion with extended knees: 5° dorsiflexion left, 5° plantar flexion right) but were not functionally limiting. Thirteen months after botulinum toxin type A treatment, the rigidity in the ankles continued to slightly increase, but the range of motion remained stable. Because the patient underwent general anesthesia for various investigations in the context of the enzyme replacement therapy (such as MRI of the spine and brain and electrophysiological investigations), we repeated the botulinum toxin type A treatment (same dosage and same location). However, the continued treatment regimen was complicated by internal hydrocephalus due to stenosis of the craniocervical junction, and the patient required placement of a ventriculoperitoneal shunt. The physical therapy regimen and follow-up treatment were not performed as required, and no casting was possible after the second botulinum toxin type A treatment. Nevertheless, his gait improved significantly, the range of motion increased continuously (5° dorsiflexion right, 0° dorsiflexion left with extended knees), and the ankle–foot orthoses were better tolerated.
Case 2
The boy was born at term after a normal pregnancy and perinatal period. He was first referred to the pediatric surgery department because of recurrent inguinal hernias at the age of 3 months. At the age of 17 months, he received a consultation in the neuropediatric ward because of progressive gait abnormalities and a mild developmental delay. The neurological examination revealed a coarse face, torticollis to the right side, spasticity of the lower extremities with elevated, broadened reflexes, positive Babinski reflexes on both sides, and a slight shortening of the gastrocnemius muscle on the left side. His liver could be palpated 3 cm below the costal arch. Mucopolysaccharidosis was suspected. He did not have iduronat-2-sulfatase activity in the serum or leukocytes, and mucopolysaccharidosis type II was diagnosed. At the age of 22 months, he showed normal cognitive development. However, the gait abnormalities worsened, and he developed a marked equinus gait, especially on his left foot. The range of motion in his ankle joint decreased (ankle dorsiflexion with stretched knees, 10° left, normal range of motion right; ankle dorsiflexion with extended knee, 0° left, normal range right).
Ultrasound-guided botulinum toxin type A injections under general anesthesia were performed to improve gait performance and the range of motion in the left ankle joint. A total dosage of 95 U of botulinum toxin type A (Botox), which corresponded to 7.0 U per kilogram of body weight, was injected using a dilution of 50 U of botulinum toxin type A per milliliter of 0.9% sodium chloride (M soleus left, 1 injection site, 1 × 35 U; medial and lateral head of the M gastrocnemius left, 1 injection site per muscle belly, 1 × 30 U each). The parents gave oral informed consent for this off-label use of botulinum toxin type A therapy. The patient was further treated by serial casting for 4 weeks, and intensified physical therapy was prescribed. Six weeks after the botulinum toxin type A treatment, the range of motion had improved (ankle dorsiflexion with extended knees left, 10°), and the patient’s gait performance had significantly improved. In addition, he was treated with ankle–foot orthoses, and 8 months after botulinum toxin type A treatment, he walked with initial heel landing and complete foot–floor contact with and without the orthoses. The range of motion had an ankle dorsiflexion of 5° left and 20° right, both with an extended knee.
Following the treatment, the patient was regularly followed in the outpatient consultancy. At the age of 6 years and 6 months, enzyme replacement therapy was initiated. His last follow-up was at the age of 9 years and 5 months. His walking ability remained stable (6-minute walking test: 600 m). He had normal tendon jerks and did not show pyramidal signs. The range of motion in the legs mostly remained stable over the years following treatment (Thomas test of 0° bilaterally, normal hip abduction and hip rotation bilaterally; ankle dorsiflexion with bent knees, 10° bilaterally; ankle dorsiflexion with extended knees, 5° dorsiflexion right, 10° dorsiflexion left). However, he developed knee flexion contractures (knee extension deficiency of 30° bilaterally). Nevertheless, under enzyme replacement therapy and physical therapy every second week, he did not require orthoses and was able to ride a bicycle and run.
Discussion
We report 2 patients with mucopolysaccharidosis type II who suffered from joint rigidity and spasticity in the calf muscles and who developed equinus foot deformity. Both patients were treated with intramuscular botulinum toxin type A injections followed by serial casting, and both patients exhibited an improvement in range of motion and an improvement in gait performance after the treatment. No side effects were observed. To our knowledge, this is the first case report on botulinum toxin type A treatment for equinus deformity in children with mucopolysaccharidosis type II. A Spanish group reported that botulinum toxin type A treatment in the psoas muscle had positive effects on the treatment of hip joint contractures in a patient with mucopolysaccharidosis type III. 17
Abnormal joint function is thought to result from a combination of metaphyseal deformities and thickened joint capsules that are secondary to glycosaminoglycan accumulation and fibrosis.4,6 Furthermore, changes in the skeletal muscle due to glycosaminoglycan accumulation can also be responsible for the limitations in the range of motion. An autopsy of 1 patient with mucopolysaccharidosis type II revealed atrophic skeletal muscles, interstitial edema in the perimysial spaces, and warping of the connective tissue. 19 Moreover, a distal neuropathy caused by the damage of the axon terminals and motor end plates led to limited function of the voluntary muscles in patients with mucopolysaccharidosis type II. 19 Spasticity in patients with mucopolysaccharidosis can be caused by cervical myelopathy and may also derive from cerebral abnormalities such as white matter lesions or hydrocephalus. A review by Muenzer et al 3 on the multidisciplinary management of Hunter syndrome therefore advises performing a spinal MRI at 1- to 3-year intervals. Whereas a cervical MRI did not show spinal abnormalities during the first years in both of the patients described in this study, patient 1 later developed spinal stenosis and malabsorptive hydrocephalus, which required the placement of a ventriculoperitoneal shunt.
Spasticity can lead to motor dysfunction and joint contractures. However, in patients with mucopolysaccharidosis, joint contractures can also develop in the absence of spasticity. Joint contractures can be found in the elbows, shoulders, wrists, hips, knees, and ankles. 6 The treatment of joint contractures in patients with mucopolysaccharidosis includes physical therapy and orthotic devices. Because patients with mucopolysaccharidosis often exhibit wound healing problems, orthopedic surgery is only performed when other treatment options lack efficacy. The benefits of physical therapy, orthotics, and orthopedic surgery have not been investigated in patients with mucopolysaccharidosis. After the initiation of enzyme replacement therapy, reduced contracture progression has been demonstrated. 5 Nevertheless, joint contractures were typically progressive and were followed by a significant functional decline. In the lower extremities, ankle joint contractures may lead to equinus foot deformities and could have negative effects on gait stability and even prevent patients from walking.
Similar to patients with mucopolysaccharidosis, patients with spastic cerebral palsy often suffer from equinus gait resulting from spasticity in the calf muscles. Botulinum toxin type A is a well-established treatment for equinus foot deformity and its negative effect on gait performance in patients with spastic cerebral palsy.13 –16,20,21 Botulinum toxin type A has been shown to prevent the release of acetylcholine from the presynaptic axon and to block signal transmission at the neuromuscular junction. The local chemodenervation results in a reversible muscle weakness. Because botulinum toxin type A in combination with serial casting was more beneficial for spasticity, gross motor function, and range of motion than botulinum toxin type A injections without casting, 22 botulinum toxin type A treatment in the calf muscles has often been combined with regression plasters. It has been shown that intramuscular botulinum toxin type A injections in the lower legs reduced spasticity and range of motion. However, compared with the reduction in spasticity, the effects on range of motion were only of short duration. 23 Therefore, it has been suggested that the development of joint contractures was not caused by increased muscle tone but depended on processes that were not directly influenced by botulinum toxin type A injections. 23 Regarding spasticity, which has been shown to contribute to increased muscle tone, significant structural alterations in the skeletal muscle, which may influence muscle stiffness, were found to occur in patients with spastic cerebral palsy. 24 In juvenile rats, it was observed that intramuscular botulinum toxin type A injections led to changes in the viscoelastic properties of the skeletal muscle. 25 However, in patients with spastic cerebral palsy, despite a positive effect on spasticity and range of motion, botulinum toxin type A did not affect muscle stiffness. 26 The adaptive processes following botulinum toxin type A injections, which influenced the muscle architecture in patients with spastic cerebral palsy, have yet to be studied in detail.
Our case reports suggest that botulinum toxin type A combined with serial casting could be a therapeutic option for the treatment of equinus foot deformity in patients with mucopolysaccharidosis type II. However, the underlying therapeutic effects of botulinum toxin type A on the skeletal muscles remain unknown. Furthermore, the long-term effects of botulinum toxin type A treatment and casting in patients with mucopolysaccharidosis are not yet determined. The functional effect of botulinum toxin type A must be studied in detail. Therefore, further studies are required to clarify the effect of intramuscular botulinum toxin type A in patients with mucopolysaccharidosis. Those studies should include larger patient groups, document possible side effects, and assess the effect of the treatment with respect to gait changes, spasticity, stiffness, and range of motion using objective and reliable outcome measures, such as 3-dimensional gait analysis. Furthermore, functional benefits should be assessed using standardized clinical measures. The therapeutic effects of botulinum toxin type A treatment and casting, such as possible changes in muscle architecture, have yet to be clarified in patients with mucopolysaccharidosis.
Conclusion
Botulinum toxin type A combined with serial casting might represent a therapeutic option for the treatment of equinus deformity in patients with mucopolysaccharidosis type II. However, prospective clinical trials are required to clarify the detailed effects of botulinum toxin type A on spasticity, muscle stiffness, range of motion, gait performance, and gross motor function. The pathophysiological changes after botulinum toxin type A injections that may lead to an improvement in range of motion and gait performance must be examined in detail.
Footnotes
Acknowledgments
This work was performed at the University Children’s Hospital Berne and Basel.
Author Contributions
The first draft of the manuscript was written by EN and SG. PW, MG, and J-MN critically revised the manuscript for important intellectual content. All authors have approved the final version to be published.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
As the initial intention was not to perform a case series study but to observe the clinical effect of the off-label use of botulinum toxin type A, no ethical approval was obtained. The parents of both children gave oral informed consent for this new mode of therapy after we explained to them the advantages and disadvantages of botulinum toxin type A therapy.