Eur J Pediatr DOI 10.1007/s00431-013-2151-z
SHORT COMMUNICATION
Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy Ferdinando Ceravolo & Sonia Messina & Carmelo Rodolico & Pietro Strisciuglio & Daniela Concolino
Received: 15 July 2013 / Accepted: 13 August 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Myoglobinuria is a frequent complication of metabolic myopathies and may also occur in Duchenne and Becker dystrophies but is not a typical sign of limb–girdle muscular dystrophy. We describe an unusual presentation of alphasarcoglycanopathy with myoglobinuria at the onset of the disease. The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics. He was admitted to the hospital and investigated for post-infectious nephritis, but further analysis revealed the presence of myoglobinuria. Immunohistochemistry on muscle tissue revealed absent expression of α-sarcoglycan confirmed by detection of a homozygous mutation in the alphasarcoglycan gene. Myoglobinuria has been previously reported four times in sarcoglycanopathies but only once in alphasarcoglycanopathy. Conclusion The present observation reinforces the idea that the myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy even as the only recognizable sign at the debut of the disease. Keywords Sarcoglycanopathy . Muscular dystrophy . Neuromuscular disorders . Myoglobinuria
F. Ceravolo (*) Operative Unit of Metabolic Disease, Bambino Gesù Children’s Hospital, Rome, Italy e-mail:
[email protected] S. Messina : C. Rodolico Department of Neurosciences, University of Messina, Messina, Italy P. Strisciuglio Department of Pediatrics, University “Federico II” of Naples, Naples, Italy D. Concolino Department of Pediatrics, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
Introduction Limb–girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases characterized by progressive weakness and atrophy of the proximal muscles. They are due to mutations in 1 of the 25 gene encoding proteins involved in maintaining the integrity of the muscle cells (http:// neuromuscular.wustl.edu/musdist/lg.html.). Based on the pattern of inheritance, LGMD are divided into two groups, autosomal dominant LGMD1 (A-H) and autosomal recessive form LGMD2 (A-Q). The sarcoglycanopathies (LGMD2 CF) belong to the group of autosomal recessive forms and are caused by defects in one of the four genes encoding the transmembrane glycoproteins alpha, beta, gamma, and delta sarcoglycan. These four protein subunits form a tetrameric complex that interacts with dystrophin and other muscle proteins (dystrophin–glycoprotein complex) and whose role seems to be to stabilize the sarcoplasmic membrane during cycles of contraction and relaxation of the muscle, to link the contractile force generated by the fiber with the extracellular environment and to maintain the topology of membrane proteins in the course of contractile activity. Clinical forms range from the “Duchenne muscular dystrophy-like” with early onset, severe progression and frequent cardiac involvement to milder ones with later onset, slower progression and milder clinical signs. A myopathic or dystrophic pattern can be present on muscle biopsy. Immunohistochemistry with antibodies directed against alpha, beta, gamma, and delta sarcoglycans may be helpful in revealing the absence or severe reduction of the staining for α-sarcoglycan and a reduction of the other components. Severity of phenotype usually correlates with the expression of α-sarcoglycan in the muscle [10, 11]. However, abnormal staining of multiple components reflects the destabilization of the entire dystrophin–glycoprotein complex by the protein that is abnormal in the particular type of sarcoglycanopathy [5]. Myoglobinuria,
Eur J Pediatr
secondary to rhabdomyolysis, is a typical sign in many metabolic myopathies but may also be present in some muscular dystrophies such as Duchenne, Becker, LGMD2B, and LGMD2I. In these cases, myoglobinuria occurred as a consequence of strength exercise and is usually accompanied by elevated levels of creatine kinase and muscular pain [6, 9]. Myoglobinuria is rare in sarcoglycanopathies as it has been reported only in four cases [1, 2, 7, 8], and among those, only one had a diagnosis of α-sarcoglycanopathy [7]. We describe an unusual case of alpha-sarcoglycanopathy with myoglobinuria as the only sign at onset of the disease and a very mild progression in spite of absence of α-sarcoglycan expression in muscle.
sarcoglycans in the patient (Fig. 1). These data suggested a pathology of the sarcoglycan protein complex; molecular analysis of the beta, gamma, and delta sarcoglycans were normal; analysis of the alpha-sarcoglycan gene on chromosome 17q21.33 revealed an homozygous C-T pair base substitution at nucleotide 299 in exon 3 (R77C) confirming the diagnosis of primary alpha-sarcoglycanopathy. At last follow-up at 8 years of age, the patient showed a mild waddling gait with lumbar hyperlordosis and slightly positive Gower’s maneuver. During recent evaluations, serum CK was consistently elevated (8,000–12,000 U/L)
Discussion Case report This 5-year-old boy had an episode of dark urine 10 days after having fever and sore throat treated with antibiotics. A urine hemastix performed in a pediatric ambulatory showed the presence of blood (++++), and for this reason, the patient was hospitalized the next day and investigated for postinfectious nephritis. Laboratory examinations, including urinalysis, show only a mild elevation of serum AST and ALT. This made the initial diagnostic hypothesis unlikely, and he was then referred to our department for further evaluation. The patient is the second child of healthy consanguineous parents (second cousins) with no family history of noteworthy diseases. He was always in good health and achieved all developmental milestones appropriately. No history of weakness or muscle cramps was reported. On physical examination, the boy appeared in good health, and the neuromuscular examination showed only a mild and asymptomatic scapular winging. Laboratory investigations confirmed the elevation of AST 255 U/L (nl 5–45) and ALT 516 U/L (nl 15–55) but also showed elevated serum CK 10,268 U/L (nl
