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
- Registration Number
- NCT04007562
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
- 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
- Opposition of parental authority holders
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Lipin-1 deficiency Hydroxychloroquine Sulfate Patients suffering from Lipin-1 deficiency havebenefited from an off-label use treatment by Hydroxychloroquine Sulfate as part of their care for at least 6 months.
- Primary Outcome Measures
Name Time Method Inflammatory cytokines in plasma 36 months Quantitative flow cytometry based mutliplex assays (flow cytometry-based systems (BD™ Cytometric Bead Array)).
Quantification of mitochondrial DNA in plasma 36 months Quantitative PCR to detect mitochondrial DNA, 12s gene.
Creatine kinase dosage in plasma 36 months
- Secondary Outcome Measures
Name Time Method Occurrence of muscular fatigability 36 months Clinical examination.
Occurrence of adverse effect 36 months Patient interrogation.
Assessment of pain: VAS 36 months Visual analogue scale (VAS) : scale from 1 to 10; compare from one examination to another for a patient (which is his own control).
Quality-of-life assessment: Pediatric Quality of Life InventoryTM (PedsQL) questionnaire 36 months Pediatric Quality of Life InventoryTM (PedsQL) questionnaire adapted to age: child questionnaire and parent questionnaire. Questionnaire of 23 questions scored on 5 points, from 0 (never) to 4 (almost always). The scores are linearly transformed on a scale between 0 and 100, added together and divided by the number of items completed; high scores are associated with a better quality of life related to health.
Dosing of Hydroxychloroquine Sulfate in plasma 36 months Compliance.
Quotation of the different muscles 36 months Muscle testing by a physiotherapist.
6-min walking test 36 months Absence of cardiac arrhythmia 36 months Electrocardiography
Occurrence of rash 36 months Clinical examination.
Occurence of retinopathy. 36 months Fundus eye and electroretinogram.
Occurrence of intercurrent event 36 months Clinical examination.
Test of the number of steps during a 3-min walk 36 months Gowers sign appearance 36 months Clinical examination.
Occurrence of shortness of breath 36 months Clinical examination.
Treatment compliance 36 months Patient interrogation.
Echocardiography 36 months Measurement of the wall of the ventricles, ejection fraction.
Trial Locations
- Locations (1)
Hôpital Necker-Enfants Malades
🇫🇷Paris, France