acute rhabdomyolysis and muscle pain associated with mutations in the lpin1 gene - a retrospective study describing the safety and efficacy of hydroxychloroquine sulfate given on a compassionate basis to patients suffering from lipin-1 deficiency

Conditions: LIPIN1 Deficiency

Summary: lipin-1 deficiencies are responsible for severe rhabdomyolysis and muscle pain in childhood. a specific treatment does not exist. our research team (pr de lonlay, pr van-endert, marine madrange and perrine renard) identified the mechanism of this disease and propose a treatment to decrease rhabdomyolysis outcome and muscle pain. further to a cpp approval in 2015, several patients have been treated by hydroxychloroquine sulfate off label use on a compassionate basis. the objective of this retrospective study is to describe the safety and efficacy of hydroxychloroquine sulfate given on a compassionate basis to patients suffering from lipin-1 deficiency within a period between 6 and 36 months.

the lipin-1 deficiency is an inherited autosomal recessive disease caused by two mutations in the lpin1 gene. homozygous or compound heterozygous lipin-1 deficiency causes recurrent acute episodes of rhabdomyolysis and myoglobinuria in children, associated with permanent muscle pain and weakness. the onset of the disease is usually early (before the age of 6 years old) and the disease is severe. the number of acute episodes' ranges from 1 to 10 per patient, mostly during the first 6 years of life (period where illness episodes are most frequent). some patients die of myoglobinuric bouts, from cardiac arrhythmia, possibly due to hyperkalemia, with a heart probably more sensitive to hyperkaliemia. mortality rate is around 10%, and is significantly higher when rhabdomyolysis is complicated by renal failure or by cardiac arrest with arrhythmia due to hyperkalemia. a specific treatment does not exist. altogether these observations indicate that there is a crucial need to identify a treatment. our research team (pr de lonlay, pr van-endert, marine madrange and perrine renard) identified the mechanism of this disease. the consequences on myoblasts of patients are tlr9 sequestration in late endosomes and mitophagy impairment, with consecutively mitochondrial dna accumulation, tlr9 activation, inflammatory cytokines, calcium release and cell death in the presence of tlr9 ligands and a nutrient-poor environment. hydroxychloroquine sulfate, thanks to an anti-tlr9 activity restores control cell phenotypes. in vivo and in vitro results are spectacular. this treatment seems to be able to both decrease the signaling cascade resulting from the activation of tlr9 and to correct the phenotype of patients suffering from the lipin-1 deficiency. further to a cpp approval, several patients have been treated by hydroxychloroquine sulfate off label use on a compassionate basis. the objective of this retrospective study is to describe the safety and efficacy of hydroxychloroquine sulfate given on a compassionate basis to patients suffering from lipin-1 deficiency within a period between 6 and 36 months.

Eligibility criteria:
inclusion criteria: * age ≥ 3 months * minors with lipin-1 deficiency which were diagnosed with familiar context analysis followed by genetic diagnosis (two causal mutations on the lpin1 gene) and treated by hydroxychloroquine sulfate off label use on a compassionate basis in the metabolic diseases center of necker hospital * patients treated by hydroxychloroquine sulfate for at least 6 months exclusion criteria: - opposition of parental authority holders

Keywords: lipin1 deficiency acute episodes of rhabdomyolysis myoglobinuria hydroxychloroquine sulfate orphan drug