The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism

The NIH Mini Study: Metabolism, INfection and Immunity in Inborn Errors of Mitochondrial Metabolism

The Metabolism, Infection and Immunity (MINI) Study is a longitudinal natural history study at the National Institutes of Health (NIH) that aims to define the relationship between infection, immunity and clinical decline in individuals with mitochondrial disease. Mitochondrial diseases are a group of disorders caused by problems with the cell s ability to produce energy. Infection in individuals with mitochondrial disease can lead to worsening clinical symptoms, particularly neurologic symptoms.

Goals:

The main goal of our study is to understand the relationship between infection and clinical decline in patients with mitochondrial disease. Mitochondrial diseases can affect many different parts of the body, including the immune system and its ability to respond to infection. Therefore, we perform a comprehensive evaluation of participants including a detailed immunologic assessment.

We are not testing any new medicine or procedure to treat or cure IEM or mitochondrial diseases. However, by understanding the relationship between infection and mitochondrial disease, we hope to develop treatments in the future. At the NIH, we are interested in research. Although we do provide advice and care for people enrolled in our study, we are not able to take over the long-term care of participants. To enroll in our study, you (your child) must already have a confirmed diagnosis of a mitochondrial disease. We are not able to provide a "first time" diagnosis or regular metabolic care.

What is involved?

Once you contact our team members, you will be asked to provide medical records to determine eligibility. Our team will review the records and notify you if you (your child is) eligible to join the study.

-Onsite participation: You (your child) will be invited to visit the National Institutes of Health in Bethesda, Maryland. This first visit will typically last 3-5 days. Depending on the level of participation, additional visits may be requested. Our team members will work with you and your child to coordinate the supports needed during your stay at NIH. Study participants may be seen in the clinic, day hospital or inpatient setting.

When you (your child) arrive at the NIH we will have an informed consent discussion to confirm willingness to participate, answer questions and review the risks and benefits of the study. You (your child) will meet with a physician who will ask about medical and family history and do a physical exam (like in any doctor's office). We will ask all study participants to allow us to collect urine, draw blood, swab your (your child s) nose, and perform a detailed assessment. We may suggest additional evaluations or specialty consults for some participants based on clinical manifestations, age and level of independence. We will explain these studies to you (your child). They may include items such as- imaging studies, DEXA or MRI scan, energy expenditure or metabolic testing, developmental neuropsychological logical testing, physiatry, ophthalmology, or other consults. In some cases, we may request a skin biopsy (if one has not been done). You will receive the results of your (your child's) clinical testing and notes from any clinical consultations.

-Remote participation: If you (your child) are unable to travel, you (your child) may be enrolled remotely for records review, questionnaires, and telethealth exams. Blood or other samples collection may be requested in coordination with local providers or lab testing companies

Study Overview

• Status: Recruiting
• Conditions: Mitochondrial Disorders; Leigh Disease; Oxidative Phosphorylation Deficiencies; Electron Transport Chain Disorders, Mitochondrial

Detailed Description

The biochemical perturbations in children with inborn errors of metabolism (IEM) may affect their immune response. As a result, this will not only increase risk for infection but also hamper their ability to develop protective immunity after vaccination. Characterizing perturbations in immunity and the ability of vaccines to provide protective immunity in IEM is critical. Immune deficiencies and the immunogenicity of vaccines have not been well characterized in IEM.

Viral infections play a significant role in precipitating life-threatening acute decompensations in various IEM. Seasonal variation of respiratory and gastrointestinal viruses places this vulnerable population at significant risk. The standard of care for these patients is routine childhood vaccination as well as vaccination for seasonal influenza viruses. However, nutritional deficiencies and their underlying IEM enzymopathies may affect the efficacy of vaccination.

In this protocol, we will clinically evaluate the immunologic states of patients with IEM. Routine inpatient and outpatient admissions will last 2-3 days and may involve blood drawing, radiological procedures, nutrition assessment and biometrics. Immune challenge may be performed using vaccinations for seasonal influenza and pneumococcus (PPV23). Follow-up appointments will be scheduled at the end of the study period.

The study objectives will be to describe the immune deficiencies seen, in this patient population, describe vaccine seroconversion in this patient population, and search for new genes in rare families that have evidence for an unknown class of IEM. The population will consist of patients previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the patient advocacy groups. All patients will be evaluated at the NIH Clinical Center.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Shannon Kruk, R.N.; Phone Number: (301) 451-9145; Email: shannon.kruk@nih.gov
• Study Contact Backup: Name: Peter J McGuire, M.D.; Phone Number: (240) 515-5915; Email: mcguirepj@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with inborn errors of metabolism including those with mitochondrial disease

Description

• INCLUSION CRITERIA:

In order to be eligible to paraticipant in this study, an individual must meet all of the following criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study.
2. Male or female, >12 months of age.
3. Diagnosis of mitochondrial disease with documented molecular evidence of disease.
4. Healthy volunteers of any gender and ethnicity >2 years of age may also be eligible to enroll in the protocol. Healthy volunteers may be from the local community, or family members of patients with MtD.
5. Agreement to adhere to Lifestyle considerations throughout study duration.
6. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Lack of a local MtD provider (For participants with MtD only)
2. <12 months of age
3. Pregnancy or lactation
4. Discretion and clinical judgement of the Principal Investigator

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
healthy volunteers; Healthy volunteers
Inborn errors of metabolism/mitochondrial disease; patients with inborn errors of metabolism including those with mitochondrial disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To provide insight into the mechanisms involved in the interplay between the immune system and mitochondrial metabolism	By developing an understanding of immune dysfunction, targets for rational therapies may be developed for this patient population.	Initial visit and various timepoints thereafter dependent on protocol
To document the development of adaptive immunity in cohorts of mitochondrial disease patients according to the standard of care for this vulnerable population.	By developing an understanding of immune dysfunction, targets for rational therapies may be developed for this patient population.	Initial visit and various timepoints thereafter dependent on protocol

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Peter J McGuire, M.D., National Human Genome Research Institute (NHGRI)

Publications and helpful links

General Publications

• Kruk SK, Pacheco SE, Koenig MK, Bergerson JRE, Gordon-Lipkin E, McGuire PJ. Vulnerability of pediatric patients with mitochondrial disease to vaccine-preventable diseases. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2415-2418.e3. doi: 10.1016/j.jaip.2019.03.046. Epub 2019 Apr 5. No abstract available.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2012
• Primary Completion (Estimated): December 31, 2025
• Study Completion: December 31, 2025

Study Registration Dates

• First Submitted: January 29, 2013
• First Submitted That Met QC Criteria: January 29, 2013
• First Posted (Estimated): January 30, 2013

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: March 8, 2024

More Information

Terms related to this study

• Keywords: Natural History; Mitochondrial Disorders; Leigh Disease; Subacute Necrotizing Encephalopathy; Disorders of Oxidative Phosphorylation (OXPHOS)
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Pyruvate Metabolism, Inborn Errors; Mitochondrial Diseases; Leigh Disease
• Other Study ID Numbers: 130053; 13-HG-0053

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No