Paroxysmal Paralytic Rhabdomyolysis via the LPIN1 Gene, Exons 18-19 Deletion

Familial paroxysmal paralytic rhabdomyolysis with myoglobinuria (OMIM 268200), also known as childhood recurrent acute myoglobinuria is a rare and life-threatening disease of young children, in which prompt diagnosis and treatment are critical (Tein et al. Adv Pediatr 37:77-117, 1990). Early symptoms typically begin before the age of seven years and consist of generalized weakness, inability to walk, myalgia, and dark urine. Recurrent episodes of myoglobinuria are frequent features of the disease. Additional features include cardiac abnormalities, marked sensitivity over the thighs and calf muscles, muscle hypotonia, and renal failures. The episodes are triggered by febrile illnesses and persist for several days; they are characterized by concomitant elevated levels of plasma creatine kinase and aspartate aminotransferase (Ramesh and Gardner-Medwin Dev Med Child Neurol 34:73-79, 1992; Zeharia et al. Am J Hum Genet 83:489-494, 2008).

Familial cases of paroxysmal paralytic rhabdomyolysis with myoglobinuria have been reported (Christensen et al. Dan Med Bull 30:112-115, 1983; Ramesh and Gardner-Medwin Dev Med Child Neurol 34:73-79, 1992). In these families, the disease appeared to be transmitted as an autosomal recessive trait. Paroxysmal paralytic rhabdomyolysis is caused by variants in the LPIN1 gene (Zeharia et al. Am J Hum Genet 83:489-494, 2008). Variants include nonsense, missense, splicing, small deletions or insertions, and one 2-kb deletion that spans exons 18-19. This deletion appears to be common in patients of European ancestry (Michot et al. Hum Mutat 31:E1564-1573, 2010).

This deletion was found in nearly 50% of patients with detectable variants (Michot et al. Hum Mutat 31:E1564-73, 2010).

The LPIN1 gene encodes Lipin-1, phosphatidic acid phosphatase, which catalyzes the conversion of phosphatidic acid to diacylglycerol in the triacylglycerol synthesis pathway. This test involves amplification of patient DNA with a specific pair of PCR primers that flank the common LPIN1 exons 18-19 deletion. In normal chromosomes, the PCR primers are ~3 kb apart, and no PCR product is generated. From chromosomes carrying the deletion, an 860-bp PCR product is produced. PreventionGenetics also offers a sequencing test for the LPIN1 gene (Test #369).