Statin-Induced Myopathy in a Patient with Schwartz-Jampel Syndrome

Background

Schwartz-Jampel syndrome (SJS), first described in the United States in 1962, is a hereditary disorder characterized by facial dysmorphism and muscle stiffness. ¹ The prevalence is <1/million and total reported cases are <100. ² The disease exists as a lifelong disorder, and onset may become apparent after birth or through early childhood. Affected individuals can present with a range and severity of symptoms associated with myotonia and chondrodysplasia including skeletal muscle stiffness and weakness, anomalous bone, and cartilage development, and facial dysmorphism. ³ Although the exact pathophysiology of myotonia has not been elucidated, evidence suggests that a persistent opening of sodium channels might be the cause for the spontaneous depolarization, loss of functional perlecan alters the clustering of acetylcholinesterase and abnormal expression of ion channels resulting in classic myotonia and chondrodysplasia symptoms. ⁴ Patients exhibiting classic symptoms of SJS have abnormalities of bone and cartilage growth.

Studies report that mutations in the heparin sulfate proteoglycan 2 (HSPG2 gene), in chromosome 1p34-36.1, which encodes perlecan, a major element of basement membranes of muscle and cartilage, is the cause of SJS. ⁴

Case Presentation

We report a case of a 37-year-old female with a past medical history significant for statin induced myopathy and with a history of SJS confirmed by genetic testing gene: HSPG2 mutation 1 C>T 4916 (Thr1639Met) and mutation 2 C>T 8602 (Ser2201Leu) and heterozygous familial hypercholesterolemia. The patient has no known history of atherosclerotic cardiovascular disease. She has no known drug allergies. The outpatient medications that she has been stable on for several years include carbamazepine 200 mg daily and vitamin D3 1000 units orally daily. The patient was not on any over-the counter medications or supplements. A review of her labs demonstrated a baseline creatine phosphokinase (CPK) level of 230 mg/dL as well as an LDL-C of >200 mg/dL.

Initially the patient was started on rosuvastatin 20 mg by mouth daily to achieve an LDL-C reduction of <50%. Subsequently, the patient started exhibiting myopathic pains with an increase in her CPK level as high as 298 mg/dL. The rosuvastatin was stopped for 1 month and her CPK levels returned to baseline. The patient then started on evolocumab 140 mg twice monthly for 1 month. Similarly, her CPK levels started to increase to a maximum of 297 mg/dL. Evolocumab was then reduced to 140 mg once monthly with a reported CPK of 224 mg/dL. The patient was able to maintain her CPK levels close to for about 1 year before she left our treatment facility. The patient was able to achieve an LDL-C of 96 mg/dL on evolocumab 140 mg once monthly. The use of the Naranjo et al scale revealed that an adverse drug reaction was considered probable because the high intensity statin had a score of 7 of 10. ⁵ The patient was not rechallenged with rosuvastatin to further investigate the drug’s causative role. The patient demonstrated a marked resolution and reduction of LDL-C levels after the use of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, regulating serum LDL-C levels with no reported additional myopathy.

Discussion

The mutations that cause SJS reduce the amount of perlecan that is produced or lead to a version of perlecan that is only partially functional. A reduction in the amount or function of this protein disrupts the normal development of cartilage and bone tissue, which underlies chondrodysplasia in affected individuals. A reduced amount of functional perlecan at the neuromuscular junction likely alters the balance of other molecules that signal when muscles should contract and when they should relax. As a result, muscle contraction is triggered continuously, leading to myotonia. ⁶ SJS patients often present with additional manifestations including elevated CPK levels, as reported by the Human Phenotype Ontology database. ⁶ Interestingly, an elevation of this enzyme is present in clinical symptoms associated with muscle disorders including muscular dystrophy, rhabdomyolysis, and myocardial infarction. As patients with SJS exhibit myotonia, elevated CPK levels are highly conceivable. Elevated CPK can also present the following drug induction, whereas as an example, rhabdomyolysis is a rare but noted side effect of statin use. The pathophysiology of muscle related adverse events associated with statin treatment remains unknown, however, hypotheses proposing mitochondrial damage and disruptions of the HMG-CoA reductase pathway have been evidenced. ⁷

Conclusion

This case illustrates that patients with SJS may have an elevated baseline CPK levels, which may increase the risk of statin-induced myopathy. Therefore, alternative treatment with PCSK9 inhibitors once monthly may help prevent CPK elevation and lower the risk of myopathy in patients with SJS while still reducing serum LDL-C levels. Further investigation of this treatment alternative as a first line therapy in place of statin use is required for the SJS patient population.