Paroxysmal Paralytic Rhabdomyolysis via the LPIN1 Gene

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 Pediater 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. Danish 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. It 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). LPIN1 variants were reported in patients from various populations. 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 may detect variants in ~60% of patients with a clinical diagnosis as described.

This test provides full coverage of all coding exons of the LPIN1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).