Evaluate the Effort Test as a Therapeutic Monitoring Tool in Acute Rhabdomyolyses
Condition: Rhabdomyolysis Linked to a Hereditary Disease of Metabolism
MeSH terms: Rhabdomyolysis; Genetic Diseases, Inborn
Study type: Observational

Summary: 
      The prognosis of rhabdomyolyses related to hereditary diseases of metabolism is poor and
      treatments are only symptomatic. Rhabdomyolysis outbreaks are frequently precipitated by
      fever and fasting. They are unpredictable. In spite of the care of patient in an intensive
      care unit, the occurrence of renal failure and heart rhythm disorders explains a significant
      acute-phase mortality rate. There is an urgent need to understand the pathophysiological
      mechanisms of rhabdomyolyses related to hereditary diseases of metabolism, in order to
      identify specific treatments.

      Patients with rhabdomyolyses have few clinical signs outside of access. So there is a
      methodological difficulty in following a treatment test. There is an urgency to identify
      follow-up parameters in anticipation of new therapies.

      The objective of this study is to validate the hypothesis that effort test and cardiac
      function parameters are usable in the treatment monitoring for patients with acute
      rhabdomyolysis linked to a hereditary disease of metabolism and thus propose the effort test
      as an assessment tool for future clinical trials. In order to do so, the correlation between
      the results of the effort tests, performed to each patient with rhabdomyolysis related to a
      hereditary disease of metabolism, with the severity of the disease will be evaluated. This
      study is original because it opens up innovative prospects for monitoring in the field of
      hereditary diseases of metabolism, with the identification of new monitoring tools.
    

Detailed description: 
      Rhabdomyolysis is a poorly known symptom associated with the destruction of skeletal muscle
      cells. The diagnosis of rhabdomyolyses is carried when the dosage of muscle enzymes, in
      particular creatine phosphate kinase (KPC), is greater than 1000 U/L (normal < 160 U/L).

      Rhabdomyolyses may be of viral origin, but fever and viruses are also triggers of genetic
      diseases. Also, the incidence of genetic rhabdomyolyses, representing 10 to 15% of all
      rhabdomyolyses, is underestimated. Genetic causes are heterogeneous. They are mainly
      attributed to hereditary diseases of metabolism, in particular fatty acid oxidation defects,
      Lipin-1 deficiency, muscle glycogenoses, TANGO2 deficiency, mitochondrial cytopathies and
      calcium channels anomalies of in particular RYR1.

      Whatever the cause, traumatic, infectious or genetic, the rhabdomyolyses cause an alteration
      of the metabolism of adenosine triphosphate and a deregulation of the ionic channels, with
      the consequences of an intracytoplasmic calcium release and the destruction of muscle cells.

      The prognosis of rhabdomyolyses related to hereditary diseases of metabolism is poor and
      treatments are only symptomatic. Rhabdomyolysis outbreaks are frequently precipitated by
      fever and fasting. They are unpredictable. In spite of the care of patient in an intensive
      care unit, the occurrence of renal failure and heart rhythm disorders explains a significant
      acute-phase mortality rate. There is an urgent need to understand the pathophysiological
      mechanisms of rhabdomyolyses related to hereditary diseases of metabolism, in order to
      identify specific treatments.

      The pathophysiological mechanism of rhabdomyolyses related to Lipin-1 deficiency has been
      identified. Two patients with Lipin-1 deficiency treated in vivo by Hydroxychloroquine
      (Plaquenil ®, 6 mg/kg/day by one oral intake) rapidly standardized their serum inflammatory
      profile and corrected their clinical phenotype: Plasma creatine phosphokinase levels, Amount
      of mitochondrial DNA in plasma, number of myolyses, muscular pain, quality of life. One of
      these two patients, suffering from cardiac dysfunction already reported in Lipin-1 deficiency
      (left ventricular ejection fraction or LVEF 45%), significantly and durably improved cardiac
      function after one month of treatment (LVEF 62%). In addition, his fatigability and sleep
      disturbances have dramatically improved.

      Disruption of mitophagy and immunity could be a common denominator for rhabdomyolyses linked
      to hereditary diseases of metabolism, which could, despite their heterogeneity, benefit from
      a common therapeutic approach, Now non-existent. There could be a role of inflammation in
      rhabdomyolyses outbreaks of metabolic origin and new therapeutic approaches could be imagined
      as in the Lipin-1 deficiency.

      Patients with rhabdomyolyses have few clinical signs outside of access. So there is a
      methodological difficulty in following a treatment test. There is an urgency to identify
      follow-up parameters in anticipation of new therapies.

      In the Lipin deficiency, an anomaly of the effort tests with measurement of oxygen
      consumption and cardiac output was characterized. These effort tests were carried out in the
      context of care, in order to recognize for a given patient whether the practice of sport is a
      factor triggering rhabdomyolysis.

      The objective of this study is to validate the hypothesis that effort test and cardiac
      function parameters are usable in the treatment monitoring for patients with acute
      rhabdomyolysis linked to a hereditary disease of metabolism and thus propose the effort test
      as an assessment tool for future clinical trials. To date, no tests are available for
      clinical trials. In order to do so, the correlation between the results of the effort tests,
      performed to each patient with rhabdomyolysis related to a hereditary disease of metabolism,
      with the severity of the disease will be assessed, including:

      1) Metabolic flux on myoblasts, 2) clinical severity (onset of disease, number of
      rhabdomyolyses, cardiomyopathy), 3) genotype.

      This study is original because it opens up innovative prospects for monitoring in the field
      of hereditary diseases of metabolism, with the identification of new monitoring tools.
    

Intervention name(s): Effort test; Functional tests on fibroblasts
Intervention type(s): Other; Other
Intervention description(s): Cardiac function:
Echocardiography: left ventricular ejection fraction and global longitudinal strain will be measured.
Cardiopulmonary exercise test (CPET): left ventricular stroke volume was assessed noninvasively using a thoracic bioelectrical impedance device : maximal stroke volume at the peak of effort will be considered.
Peripheral muscle function:
CPET: Oxygen uptake (VO2) (and carbon dioxide) output are measured. The slope of the relationship (dQ/dVO2) will be calculated between cardiac output (Q) and VO2 using measurements of Q (using measure of the stroke volume by thoracic bioelectrical impedance device) and VO2 at rest as well as during submaximal and maximal exercise
Muscle oxygenation is measured using a near-infrared spectroscopy device.
VO2 et Q will be measured : dQ/dVO2 is high in case of oxydation defect; If Q is low because of a concommittant cardiac impairement, the DAV = VO2/Q, and DO = (Q x DAV) / (200 - DAV) will be calculated.; Functional tests performed on fibroblasts in primary culture, using as tracers of stable isotope-labeled substrates. The metabolites of interest are assayed in mass spectrometry.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The population to be studied consists of 40 patients with metabolic rhabdomyolyses followed
        by the centre of reference for metabolic diseases of the child and adult of the Necker
        Hospital.
      
Keywords: Rhabdomyolysis linked to a hereditary disease of metabolism; Correlation between the effort test and the severity of the disease and biochemical flux on myoblasts