P5.46 LPIN1 gene mutations can cause familial rhabdomyolysis and unexpected death in infancy

Abstract

Mutations in the Lipin1 gene (LPIN1 MIM#605518) are associated with the second most frequent cause of early-onset rhabdomyolysis in children. Lipin-1 is predominantly expressed in muscle and exhibits a dual role as a phosphatidate phosphatase 1 and as a transcriptional co-activator. We report on two families in whom the previously healthy siblings of the indexpatients died unexpected in early infancy. Indexpatient P1 is the second child of healthy parents. At the age of eight years the girl developed a severe rhabdomyolysis following a mild upper airway respiratory infection and prolonged physical activity. Metabolic causes of acute rhabdomyolysis were excluded. Moleculargenetic analysis revealed a compound heterozygote mutation (c.2295-863_2410-27del/c.2401C > T) in the LPIN1 gene. The elder brother of P1 had a mild episode of rhabdomyolysis following an orchidopexia at the age of three years and died acute with generalised muscle hypotonia, myalgia, vomiting and somnolence at age four years. Urine was reported to be “dark” and “liver enzymes” were elevated. Autopsy revealed signs of generalised lympho-plasmacellular infiltration of the analysed organs including the myocard. Indexpatient P2 is a four year old girl who had two episodes of rhabdomyolysis at the age of three and four years following prolonged physical activity and abrosia. Mutation analyses revealed a compound heterozygote LPIN1 mutation (c.2253_2254del/c.57C > A). The younger brother of P2 died acutely at the age of 33 months following a viral myositis four weeks prior to his death. Autopsy showed left ventricular heart failure. He had the identical compound heterozygote LPIN1 mutation as P2. Identification of LPIN1 mutations should lead to extensive testing of all siblings and consecutively careful cardiorespiratory monitoring of all molecularly diagnosed individuals although asymptomatic. Impact of LPIN1 mutations in (pediatric) patients with sudden death syndrome is unclear.