Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups.

Introduction Of nearly 38 million people in the U.S. receiving statin therapy, 0.1–0.5% experience severe or life-threatening myopathic side effects. Methods We performed a genome-wide association study (GWAS) in patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. Results Replication studies in independent groups of severe statin myopathy (n=190) and statintolerant controls (n=130) resulted in the identification of three SNPs, rs9342288, rs1337512 and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (p=0.0003–0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. Discussion Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle.

The statins have emerged as the dominant class of drug for the treatment of hypercholesterolemia. These medications are generally well tolerated. However, myalgias, the most frequent side-effect, occur in up to 7% of patients. 1 Transaminitis and skeletal myotoxicity, with elevated serum creatine kinase (CK) levels (i.e., >10 times the upper limit of normal), occur with reported frequencies of 1% and 0.1%, respectively. 2 Various hypotheses have been proposed to explain the relationship between statin therapy and the spectrum of muscle dysfunction manifested by myalgia, myopathy, and rhabdomyolysis.Statin-mediated inhibition of mevalonate metabolism impairs the synthesis of isoprenylated products−the most notable of which is ubiquinone. However, isoprenylation is responsible for the post-translational modification of up to 2% of cellular proteins. 3 Therefore, numerous metabolic pathways are potentially modified by statin-mediated hypoprenylation. Subclinical defects in one or more energy-deriving pathways may be unmasked upon exposure to the pleotropic effects of statins. Such pharmacogenomic synergism may underlie the development of "statin myopathy" in a subset of patients. In this regard, we describe four patients with mutations in the myophosphorylase (PYGM; MIM 232600), myoadenylate deaminase (AMPD1; MIM 102770), and carnitine palmitoyltransferase (CPT2; MIM 600650) genes whose diagnoses became apparent during the course of investigations for statin-induced myalgias and hyperCKemia. CASE REPORTSPatient A, a 70-year-old Italian male, was found to have a high CK activity (416 U/L) on routine blood work approximately one year following initiation of cerivastatin. A repeat CK measured 1516 U/L and the statin was discontinued after which the CK dropped to 287 U/L five months later. Over the next eight months his CK remained elevated with the nadir of 488 U/L. He consistently reported proximal muscle aches with slight weakness on stair climbing and easy fatigability with moderate intensity activities. These symptoms were exaggerated during statin exposure and improved after discontinuation of the statin and coincident coenzyme Q10 supplementation (60 mg twice daily). Neurologic examination was normal. Specifically, there was no evidence of ptosis, ophthalmoparesis, dysphagia, or neck extensor weakness. Muscle stretch reflexes and sensation were intact. He manifested mild hip flexor weakness. Nerve conduction studies and electromyography (EMG) were normal. Ergometry and forearm ischemic testing were not performed. Metabolic Myopathies Discovered During Investigations of Statin Myopathy PEER REVIEWED LETTERPeriodic acid Schiff reaction demonstrated increased glycogen. Muscle histochemistry revealed absent staining for myophosphorylase activity. Neither ragged-red nor cytochrome oxidase negative fibers were observed. Oil red O staining revealed normal intramyocellar lipid content. Routine adenosine triphosphatase staining did not reveal type I fiber atrophy. Rare mitochondrial paracrystalline inclusions were evide...

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder with a mortality rate approaching 60% in the first year. The median survival is 14 months from the time of diagnosis. Although a variety of chemotherapeutic regimens have been utilized, there is no standard treatment. Studies have shown that in most cases the malignant cells are B-cells, which induce massive infiltration of reactive T-lymphocytes in the background. The disease is therefore considered as a T-cell rich B-cell lymphoproliferative disorder. We report a case of LYG with pulmonary, hepatic, central and peripheral nervous system involvement that was successfully treated with the anti-CD20 (B-cell) monoclonal antibody, Rituximab.