Applying pGz in Mitochondrial Disease

Aim 1 Enrollment Criteria Inclusion Criteria for Healthy Controls

• Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm
• Ambulatory and able to complete routine clinical exercise testing
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for PMD Patients

• Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm
• Ambulatory and able to complete routine clinical exercise testing
• Willing and able to complete all study procedures
• Genetically confirmed mitochondrial myopathy (MM) as defined by a diagnosis of primary mitochondrial disease (PMD) with predominant symptoms of myopathy as expressed by exercise intolerance and muscle weakness and fatigue
• Parental/guardian permission (informed consent) and as appropriate, child assent

Exclusion Criteria for All Aim 1 Participants General Exclusion Criteria

• Tracheostomy
• Non-ambulatory
• Unable to complete routine exercise testing
• Diagnosed with or have symptoms of vertigo
• Within 1 month of a recent hospital admission for acute illness
• Severe co-existing cardiac or pulmonary disease
• Cognitive impairment that may preclude ability to comply with study procedures
• Pregnant or lactating females
• Active alcohol and/or substance abuse
• At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures
• Use of investigational agent(s) within 4 weeks
• Individuals who are employed by the U.S. Department of Defense, including U.S military personal
• Patients with biliary atresia with asplenia or polysplenia.
• Patients with prior liver transplant.
• Patients with cystic fibrosis.
• Patients with chronic lung disease.
• Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein.
• Patients with significant heart disease or severe congenital heart disease.
• Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent
• Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation
• Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation
• Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite)
• Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces
• Inability to lie flat in an MRI scanner for up to 45 minutes
• Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study

Aim 2 Enrollment Criteria Inclusion Criteria for PICU PMD Non-Ambulatory Patients

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• Genetically confirmed mtDNA-PMD
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for PICU non-PMD neuromuscular diagnosis

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• Genetically confirmed non-PMD neuromuscular diagnosis
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for all other PICU Participants

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• No known genetic diagnosis with healthy pre-morbid status, admitted to PICU
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Exclusion Criteria for All Aim 2 Participants

• Have cognitive impairment that may preclude ability to comply with study procedures
• Have cardiorespiratory instability
• Patients in whom are so sick that they will not be able to cooperate with the study procedures
• Have clear contraindications to mobilization
• Have fixed lower limb deformities/contractures that would prohibit lower extremity exercise
• Pregnant or lactating females
• Active alcohol and/or substance abuse
• At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study
• Use of investigational agent(s) within 4 weeks
• Individual who are employed by the U.S. Department of Defense, including U.S military personal
• Patients with biliary atresia with asplenia or polysplenia.
• Patients with prior liver transplant.
• Patients with cystic fibrosis.
• Patients with chronic lung disease.
• Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein.
• Patients with significant heart disease or severe congenital heart disease.
• Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent

Exclusion Criteria Specific to study procedure: CrCEST MRI Scan:

• Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation
• Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation
• Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite)
• Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces
• Inability to lie flat in an MRI scanner for up to 45 minutes
• Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study