Myoglobinuria and muscle pain are common in patients with limb-girdle muscular dystrophy 2I

Fukutin-related protein (FKRP; OMIM #606596) is critical for the appropriate glycosylation of α-dystroglycan, a component of the dystrophin-glycoprotein complex. The 12-kb FKRP gene is composed of 3 noncoding exons and 1 exon encompassing the entire open reading frame.¹ Mutations in FKRP cause autosomal recessive muscular dystrophy with a wide range of clinical severity. A common missense mutation, c.826C>A (p.L276I), has been identified. Generally, individuals homozygous for this mutation have a mild form of limb-girdle muscular dystrophy (LGMD) 2I, compound heterozygotes with 1 c.826C>A allele have a more severe form of LGMD 2I, and those with 2 unique alleles are most severely affected, including some with congenital muscular dystrophy.^1,2

We report a high incidence of myoglobinuria and muscle pain in a retrospective study of patients with LGMD 2I.

Methods.

Standard protocol approvals, registrations, and patient consents.

Institutional Review Board approval was obtained for all recruitment and data collection. Written informed consent was obtained from all participants or their legal guardians. This study was posted on clinicaltrials.gov (NCT00313677). All patients with FKRP mutations were eligible for enrollment from 2006 to the present.

Genetic testing.

FKRP mutations were confirmed in the University of Iowa Molecular Pathology Laboratory using an amplification-refractory mutation system (ARMS) assay, direct sequencing, or both. The ARMS assay identifies the c.826C>A FKRP variant and common point mutations in SCGA (c.229C>T in LGMD2D) and SCGB (c.341C>T in LGMD2E). Primer sequences and technical details are provided in appendix e-1 on the Neurology® Web site at www.neurology.org.

Clinical evaluation.

Participants completed a questionnaire and interview regarding medical history and activities. Medical records were reviewed and selected items including age at onset, presenting symptoms, comorbidities, and laboratory testing were abstracted to a secure database. All participants were specifically asked about any episodes of “cola-colored” or brown urine, and details surrounding the event.

Results.

Twenty-six LGMD 2I patients have enrolled. Fourteen (54%) are homozygous for the c.826C>A mutation and 12 (46%) are heterozygous with 1 c.826 C>A allele and 1 other pathogenic allele. Self-reported age at onset of weakness was 13.6 ± 8.5 years for c.826C>A homozygotes, compared to 4.3 ± 3.5 years for patients with only 1 copy of the c.826C>A allele. Serum creatine kinase (CK) levels not associated with myoglobinuria ranged from 1,193 to 18,474 IU.

Seven patients (27%) have had at least 1 episode of myoglobinuria by self-report. Six of these 7 (86%) are homozygous for the c.826C>A mutation. Clinical features of those with myoglobinuria are summarized in the table. In 3 cases, the first bout of myoglobinuria led to the diagnosis of muscular dystrophy. In other patients, myoglobinuria occurred many years prior to diagnosis of muscular dystrophy, usually because patients did not report the problem to medical personnel (see the table). The first episode of myoglobinuria occurred before age 18 years in 6 individuals, and was precipitated by physical activity. No one in this group is known to have sustained renal damage. Serum CK as high as 56,000 IU was recorded in association with myoglobinuria.

Table.

Clinical characteristics of patients with myoglobinuria

^aTwo patients reported tea- or cola-colored urine associated with most athletic workouts over many years. (One viewed this as a sign that he had a good workout.)

Sixteen patients (61%) of the cohort reported significant muscle pain or cramps as part of their symptom complex, including 6 with myoglobinuria and 10 without. Eleven patients (69%) with myalgia are homozygous for c.826A>C and 5 (31%) are compound heterozygotes. Muscle pain, like myoglobinuria, was typically associated with physical exertion.

Discussion.

Myoglobinuria and muscle pain were common features of the LGMD 2I phenotype in our series. Other series have variably reported myalgia^1–5 but 2 large series found a strikingly similar incidence of myoglobinuria (∼25% of patients).^4,5

Of the patients with myoglobinuria described here and in the literature, all but 2 are homozygous for the common c.826C>A allele. These patients, with a milder phenotype, may engage in more vigorous activity (see activities listed in the table) and thus precipitate rhabdomyolysis. A similar pattern is seen in dystrophinopathy, where up to 37% of minimally symptomatic patients reported myoglobinuria,⁶ compared to rare reports in typical Duchenne muscular dystrophy.

We note that one of our patients, and at least 3 others in the literature,^5,7 experienced anesthetic reaction suggestive of malignant hyperthermia. It will be important to clarify the frequency of this potential complication in future series.

Myoglobinuria can be precipitated by a wide variety of insults in healthy muscle or can be associated with myopathy. An underlying FKRP mutation should be considered in patients presenting with childhood-onset myoglobinuria who have sustained elevation of CK (>5× normal). In addition, management of patients with LGMD 2I should include specific questions about myalgia and myoglobinuria.