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.1Transaminitis 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.2Various
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.3Therefore, 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
palmitoyltransferase (CPT2; MIM 600650) genes whose
diagnoses became apparent during the course of investigations
for statin-induced myalgias and hyperCKemia.
Patient 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/Lfive 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
Steven K. Baker, Georgirene D. Vladutiu, Wendy L. Peltier, Paul J. Isackson, Mark A. Tarnopolsky
Can. J. Neurol. Sci. 2008; 35: 94-97
PEER REVIEWED LETTER
Periodic acid Schiff reaction demonstrated increased glycogen.
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 evident with
electron microscopy. Glycogen granule accumulation was noted
in the subsarcolemmal and intermyofibrillary compartments.
Mutation analysis demonstrated homozygosity for the R50X
mutation in exon 1 of the PGYM gene at chromosome 11q13
confirming a diagnosis of McArdle disease and carrier status for
the Q12X mutation in exon 2 of the AMPD1 gene on
chromosome 1p21-13 was found .
Patient B, a 53-year-old athletic man with a history of
essential hypertension and familial hypercholesterolemia,
reported exercise intolerance, exertional cramps, and fatigue
three months after initiating atorvastatin therapy (20 mg). The
initial CK was elevated at 2,990 U/L and subsequently declined
to normal several weeks after discontinuation. Symptoms
persisted and he experienced mild CK elevations in response to
day-surgery and E. Coli gastroenteritis.
There was no family history of neuromuscular disease and his
physical examination was normal. Screening blood work
revealed normal values for the following: erythrocyte
sedimentation rate, complete blood count, electrolytes, lactate,
pyruvate, homocysteine, anti-nuclear antibody, and carnitine
levels (free, esterified, and total). Electrophysiologic studies
demonstrated normal sensory and motor nerve function. Subtle
small brief early recruiting motor unit action potentials were
observed in proximal muscles on needle electromyography.
Biopsy of the right vastus lateralis revealed mild variability in
fiber size and rare ring fibers. There was dense uptake of
From the Department of Medicine (SKB), Department of Pediatrics (MAT),
Neuromuscular Disease Clinic, McMaster University, McMaster University Medical
Center, Hamilton, Ontario, Canada; Departments of Pediatrics, Neurology, and
Pathology (GDV, PJI), School of Medicine and Biomedical Sciences, State University
of New York at Buffalo, Buffalo, New York; Department of Neurology (WLP),
Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
RECEIVED JANUARY 24, 2007. FINAL REVISIONS SUBMITTED OCTOBER 16, 2007.
Reprint requests to: S. K. Baker, Department of Medicine (Physical Medicine &
Neurology, Rm 2H22), McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.